Salts and crystalline forms of an apoptosis-inducing agent

ABSTRACT

Salts and crystalline forms of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide are suitable active pharmaceutical ingredients for pharmaceutical compositions useful in treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No.61/416,656, filed Nov. 23, 2010, which is hereby incorporated byreference as if set forth in its entirety.

Cross-reference is also made, without claim to benefit of priority oradmission as to prior art status, to the following pending U.S.application containing subject matter related to the presentapplication: Ser. No. 12/787,682 (published as U.S. 2010/0305122) titled“Apoptosis-inducing Agents for the Treatment of Cancer and Immune andAutoimmune Diseases,” the entire disclosure of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to salts and crystalline forms of anapoptosis-inducing agent, to pharmaceutical dosage forms comprising suchsalts and crystalline forms, to processes for preparing salts andcrystalline forms, and to methods of use thereof for treating diseasescharacterized by overexpression of anti-apoptotic Bcl-2 family proteins.

BACKGROUND OF THE INVENTION

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem.

Evasion of apoptosis is a hallmark of cancer (Hanahan & Weinberg (2000)Cell 100:57-70). Cancer cells must overcome a continual bombardment bycellular stresses such as DNA damage, oncogene activation, aberrant cellcycle progression and harsh microenvironments that would cause normalcells to undergo apoptosis. One of the primary means by which cancercells evade apoptosis is by up-regulation of anti-apoptotic proteins ofthe Bcl-2 family.

A particular type of neoplastic disease for which improved therapies areneeded is non-Hodgkin's lymphoma (NHL). NHL is the sixth most prevalenttype of new cancer in the U.S. and occurs primarily in patients 60-70years of age. NHL is not a single disease but a family of relateddiseases, which are classified on the basis of several characteristicsincluding clinical attributes and histology.

One method of classification places different histological subtypes intotwo major categories based on natural history of the disease, i.e.,whether the disease is indolent or aggressive. In general, indolentsubtypes grow slowly and are generally incurable, whereas aggressivesubtypes grow rapidly and are potentially curable. Follicular lymphomasare the most common indolent subtype, and diffuse large-cell lymphomasconstitute the most common aggressive subtype. The oncoprotein Bcl-2 wasoriginally described in non-Hodgkin's B-cell lymphoma.

Treatment of follicular lymphoma typically consists ofbiologically-based or combination chemotherapy. Combination therapy withrituximab, cyclophosphamide, doxorubicin, vincristine and prednisone(R-CHOP) is routinely used, as is combination therapy with rituximab,cyclophosphamide, vincristine and prednisone (RCVP). Single-agenttherapy with rituximab (targeting CD20, a phosphoprotein uniformlyexpressed on the surface of B-cells) or fludarabine is also used.Addition of rituximab to chemotherapy regimens can provide improvedresponse rate and increased progression-free survival.

Radioimmunotherapy agents, high-dose chemotherapy and stem celltransplants can be used to treat refractory or relapsed NHL. Currently,there is not an approved treatment regimen that produces a cure, andcurrent guidelines recommend that patients be treated in the context ofa clinical trial, even in a first-line setting.

First-line treatment of patients with aggressive large B-cell lymphomatypically consists of rituximab, cyclophosphamide, doxorubicin,vincristine and prednisone (R-CHOP), or dose-adjusted etoposide,prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab(DA-EPOCH-R).

Most lymphomas respond initially to any one of these therapies, buttumors typically recur and eventually become refractory. As the numberof regimens patients receive increases, the more chemotherapy-resistantthe disease becomes. Average response to first-line therapy isapproximately 75%, 60% to second-line, 50% to third-line, and about35-40% to fourth-line therapy. Response rates approaching 20% with asingle agent in a multiple relapsed setting are considered positive andwarrant further study.

Other neoplastic diseases for which improved therapies are neededinclude leukemias such as chronic lymphocytic leukemia (like NHL, aB-cell lymphoma) and acute lymphocyctic leukemia.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. CLLis primarily a disease of adults, more than 75% of people newlydiagnosed being over the age of 50, but in rare cases it is also foundin children. Combination chemotherapies are the prevalent treatment, forexample fludarabine with cyclophosphamide and/or rituximab, or morecomplex combinations such as CHOP or R-CHOP.

Acute lymphocytic leukemia, also known as acute lymphoblastic leukemia(ALL), is primarily a childhood disease, once with essentially zerosurvival but now with up to 75% survival due to combinationchemotherapies similar to those mentioned above. New therapies are stillneeded to provide further improvement in survival rates.

Current chemotherapeutic agents elicit their antitumor response byinducing apoptosis through a variety of mechanisms. However, many tumorsultimately become resistant to these agents. Bcl-2 and Bcl-X_(L) havebeen shown to confer chemotherapy resistance in short-term survivalassays in vitro and, more recently, in vivo. This suggests that ifimproved therapies aimed at suppressing the function of Bcl-2 andBcl-X_(L) can be developed, such chemotherapy-resistance could besuccessfully overcome.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, CLL, colorectal cancer,esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer,non-small cell lung cancer, prostate cancer, small cell lung cancer,spleen cancer and the like is described in International PatentPublication Nos. WO 2005/024636 and WO 2005/049593.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed, for example, by Puck & Zhu (2003) Current Allergy and AsthmaReports 3:378-384; Shimazaki et al. (2000) British Journal ofHaematology 110(3):584-590; Rengan et al. (2000) Blood 95(4):1283-1292;and Holzelova et al. (2004) New England Journal of Medicine351(14):1409-1418. Involvement of Bcl-2 proteins in bone marrowtransplant rejection is disclosed in United States Patent ApplicationPublication No. US 2008/0182845.

Compounds that occupy a binding site on Bcl-2 proteins are known. To betherapeutically useful by oral administration, such compounds desirablyhave high binding affinity, exhibiting for example K_(i)<1 nM,preferably <0.1 nM, more preferably <0.01 nM, to proteins of the Bcl-2family, specifically Bcl-2, Bcl-X_(L) and Bcl-w. It is further desirablethat they be formulated in a manner that provides high systemic exposureafter oral administration. A typical measure of systemic exposure afteroral administration of a compound is the area under the curve (AUC)resulting from graphing plasma concentration of the compound versus timefrom oral administration.

Apoptosis-inducing drugs that target Bcl-2 family proteins such as Bcl-2and Bcl-X_(L) are best administered according to a regimen that providescontinual, for example daily, replenishment of the plasma concentration,to maintain the concentration in a therapeutically effective range. Thiscan be achieved by daily parenteral, e.g., intravenous (i.v.) orintraperitoneal (i.p.) administration. However, daily parenteraladministration is often not practical in a clinical setting,particularly for outpatients. To enhance clinical utility of anapoptosis-inducing agent, for example as a chemotherapeutic in cancerpatients, a dosage form with acceptable oral bioavailability would behighly desirable. Such a dosage form, and a regimen for oraladministration thereof, would represent an important advance intreatment of many types of cancer, including NHL, CLL and ALL, and wouldmore readily enable combination therapies with other chemotherapeutics.

Different crystalline forms of an apoptosis-inducing agent can providedifferent properties with respect to stability, solubility, dissolutionrate, hardness, compressibility and melting point, among other physicaland mechanical properties. Because ease of manufacture, formulation,storage and transport of an apoptosis-inducing agent is dependent on atleast some of these properties, there is a need in the chemical andtherapeutic arts for identification of new salts and crystalline formsof apoptosis-inducing agents and ways for reproducibly generating suchsalts and crystalline forms.

SUMMARY OF THE INVENTION

The present disclosure relates to salts and crystalline forms of anapoptosis-inducing agent, referred to herein as “Compound 1,” which hasthe systematic name4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide,and which can be depicted by the formula:

Following synthesis of Compound 1, as described herein, the product maybe recovered as a powder in an amorphous state. An amorphous form ofCompound 1 may not be well suited for use as an active pharmaceuticalingredient (API) for various types of downstream formulations. Moreparticularly, an amorphous form of Compound 1 can be difficult andtherefore expensive to purify and can present process control problems.

The present disclosure provides a series of novel salts and crystallineforms of Compound 1 suitable for use as API in a wide variety offormulation types, including those where the API is present inparticulate form together with excipients, for example in orallydeliverable tablets or capsules. The salts and crystalline forms ofCompound 1 may also be useful where the crystalline form is converted toa non-crystalline form (e.g., solution or amorphous form) whenformulated. Also included are ways to prepare the salts and crystallineforms of Compound 1. Salt and crystalline forms of Compound 1 can beused to modulate and/or improve the physicochemical properties of theAPI, including solid state properties (e.g., crystallinity,hygroscopicity, melting point, hydration potential, polymorphism, etc.),pharmaceutical properties (e.g., solubility/dissolution rate, stability,compatibility, etc.), and crystallization characteristics (e.g., purity,yield, morphology, etc.), as non-limiting examples.

In some embodiments, the salt or crystalline form of Compound 1 includesthose of Compound 1 free base anhydrate having PXRD pattern A, Compound1 free base anhydrate having PXRD pattern B, Compound 1 free basehydrate having PXRD pattern C, Compound 1 free base hydrate having PXRDpattern D, Compound 1 free base dichloromethane solvate having patternE, Compound 1 free base ethyl acetate solvate having PXRD pattern F,Compound 1 free base ethyl acetate solvate having PXRD pattern G,Compound 1 free base acetonitrile solvate having PXRD pattern H,Compound 1 free base acetonitrile solvate having PXRD pattern I,Compound 1 free base acetone solvate having PXRD pattern J, Compound 1hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydratehaving PXRD pattern L, Compound 1 sulfate having PXRD pattern M, andCompound 1 free base tetrahydrofuran (THF) solvate having PXRD patternN, each having the respective powder X-ray diffraction patterns asdescribed herein.

In some embodiments, the crystalline forms of Compound 1 free basedichloromethane solvate, Compound 1 free base acetonitrile solvate,Compound 1 hydrochloride, and Compound 1 free base tetrahydrofuransolvate have the respective crystal lattice parameters as describedherein.

In another embodiment, Compound 1 hydrochloride is provided.

In another embodiment, Compound 1 sulfate is provided.

In some embodiments, an API composition is provided comprising Compound1 as the API, in which at least a portion, for example at least about10%, of the Compound 1 in the composition is in a salt or crystallineform. In some embodiments, greater than 95% or essentially 100% of theAPI in such a composition is a salt or crystalline form of Compound 1.

In some embodiments, a pharmaceutical composition is provided thatcomprises a salt or crystalline form of Compound 1 as described hereinand one or more pharmaceutically acceptable excipients.

In some embodiments, a process for preparing a pharmaceutical solutioncomposition of Compound 1 is provided, where the process comprisesdissolving a salt or crystalline form of Compound 1 as described hereinwith a pharmaceutically acceptable solvent or mixture of solvents.

In some embodiments, a method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein is provided, where the method comprises administering toa subject having the disease a therapeutically effective amount of (a) asalt or crystalline form of Compound 1 as described herein or (b) apharmaceutical composition comprising a salt or crystalline form ofCompound 1 as described herein and one or more pharmaceuticallyacceptable excipients.

In some embodiments, a method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein is provided, where the method comprises preparing asolution or dispersion of a salt or crystalline form of Compound 1described herein in a pharmaceutically acceptable solvent or mixture ofsolvents, and administering the resulting solution or dispersion in atherapeutically effective amount to a subject having the disease.

Additional embodiments of the invention, including particular aspects ofthose provided above, will be found in, or will be evident from, thedetailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a PXRD scan of Compound 1 anhydrate designated pattern A.

FIG. 2 is a PXRD scan of Compound 1 anhydrate designated pattern B.

FIG. 3 is a PXRD scan of Compound 1 hydrate designated pattern C.

FIG. 4 is a PXRD scan of Compound 1 hydrate designated pattern D.

FIG. 5 is a calculated PXRD pattern of Compound 1 dichloromethanesolvate designated pattern E.

FIG. 6 is a PXRD scan of Compound 1 ethyl acetate solvate designatedpattern F.

FIG. 7 is a PXRD scan of Compound 1 ethyl acetate solvate designatedpattern G.

FIG. 8 is a calculated PXRD pattern of Compound 1 acetonitrile solvatedesignated pattern H.

FIG. 9 is a PXRD scan of Compound 1 acetonitrile solvate designatedpattern I.

FIG. 10 is a PXRD scan of Compound 1 acetone solvate designated patternJ.

FIG. 11 is a calculated PXRD pattern of Compound 1 hydrochloridedesignated pattern K.

FIG. 12 is a PXRD scan of Compound 1 hydrochloride hydrate designatedpattern L.

FIG. 13 is a PXRD scan of Compound 1 sulfate designated pattern M.

FIG. 14 is a PXRD scan of Compound 1 tetrahydrofuran solvate designatedpattern N.

DETAILED DESCRIPTION

The term “free base” is used for convenience herein to refer to Compound1 parent compound as distinct from any salt thereof, while recognizingthat the parent compound, strictly speaking, is zwitterionic at neutralconditions and thus does not always behave as a true base.

An apoptosis-inducing agent, referred to herein as Compound 1, has thesystematic name4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide,and can be depicted by the formula:

In various embodiments, salts and crystalline forms of Compound 1 areprovided. Crystalline forms include solvates, hydrates, anhydrates, andsalts of Compound 1.

In contrast to an amorphous form of Compound 1 free base and anamorphous form of a Compound 1 salt, a crystalline form is characterizedby the presence of observable peaks in a powder x-ray diffraction (PXRD)pattern measured on the crystalline form. For crystalline forms preparedto yield suitably sized single-crystals, the crystalline form can befurther characterized through an experimental determination of the unitcell parameters, the identification of the crystallographic space groupto which a single crystal belongs, or both of these. Once the unit cellparameters are known, the location of the diffraction peaks, and inparticular the 2θ values of the peaks in a PXRD pattern can becalculated, to further characterize the crystalline form. Of course, thePXRD pattern can also be measured experimentally for such crystallineforms. If not only the cell parameters but a three dimensional singlecrystal structure is known, then not only the positions but also theintensity of the peaks in the diffraction pattern can be calculated infurther characterization of the crystalline form.

The PXRD patterns measured or calculated for the salts and crystallineforms reported herein represent a fingerprint that can be compared toother experimentally determined patterns to find a match. Identity ofthe respective crystalline forms is established by overlap or match ofan experimentally determined PXRD pattern with the PXRD pattern of thecrystalline forms reported herein. In various embodiments, the salts andcrystalline forms are characterized by exhibiting at least one of thePXRD peaks reported here. Thus, in various embodiments, a salt orcrystalline form is characterized by a match of two or more peaks, amatch of 3 or more peaks, 4 or more peaks, or 5 or more peaks, and soon, from the respective PXRD patterns.

An embodiment of the synthesis of Compound 1 (free base) andrepresentative intermediate compounds is presented below. Theexemplified compounds are named using ACD/ChemSketch Version 5.06 (5Jun. 2001, Advanced Chemistry Development Inc., Toronto, Ontario),ACD/ChemSketch Version 12.01 (13 May 2009), Advanced ChemistryDevelopment Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5(CambridgeSoft, Cambridge, Mass.). Intermediates are named usingChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

Synthesis of Compound 14-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideCompound A3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g),1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) intetrahydrofuran (30 mL) were stirred overnight, neutralized withconcentrated HCl and concentrated. The residue was suspended in ethylacetate and the precipitates were collected, washed with water and driedto provide the title compound.

Compound B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoroacetic anhydride (40 mL) was added. The reaction mixturewas warmed to room temperature and stirred for 24 hours. The organiclayer was washed with brine, dried (Na₂SO₄), filtered, and concentratedto give the product.

Compound C methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

Compound B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

Compound D (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), Compound C (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with0-30% ethyl acetate/hexanes.

Compound E tert-butyl442-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl Chloride (7.5 mL) was added via syringe to Compound D (29.3 g) andtriethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixture wasstirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added andthe mixture was stirred at room temperature for 24 hours. The suspensionwas washed with brine, dried, (Na₂SO₄), filtered, and concentrated. Thecrude product was chromatographed on silica gel with 10-20% ethylacetate/hexanes.

Compound F1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

Compound E (200 mg) and triethylsilane (1 mL) were stirred indichloromethane (15 mL) and trifluoroacetic acid (15 mL) for 1 hour. Themixture was concentrated, taken up in ethyl acetate, washed twice withNaH₂PO₄, and brine, and dried (Na₂SO₄), filtered and concentrated.

Compound G 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

Compound H 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of Compound G (24.3 g) in tetrahydrofuran (500 mL) at −78°C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5mL) was added, and the mixture was allowed to warm to room temperatureover 1 hour. The reaction was poured into water, extracted three timeswith ethyl acetate, and the combined extracts were washed with brine andconcentrated. The crude product was taken up in tetrahydrofuran (200 mL)at 0° C., and 1M NaOH (69 mL) was added, followed by 30% H₂O₂ (8.43 mL),and the solution was stirred for 1 hour. Na₂S₂O₃ (10 g) was added, andthe pH was adjusted to 4-5 with concentrated HCl and solid NaH₂PO₄. Thesolution was extracted twice with ethyl acetate, and the combinedextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with5-25% ethyl acetate/hexanes.

Compound I methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of Compound H (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Compound J methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of Compound I (1.55 g), Compound F (2.42 g), and HK₂PO₄ (1.42g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24 hours. Thereaction was cooled, diluted with ether (400 mL), and washed with 3×1MNaOH, and brine, and concentrated. The crude product was chromatographedon silica gel with 10-50% ethyl acetate/hexanes.

Compound K2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

Compound J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C. wasstirred for 24 hours. The reaction was cooled, added to NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the pureproduct.

Compound L Compound 1 Free Base4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

Compound K (3.39 g), Compound A (1.87 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.39 g),and 4-dimethylaminopyridine (1.09 g) were stirred in CH₂Cl₂ (40 mL) for24 hours. The reaction was cooled and chromatographed on silica gel with25-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate with 1%acetic acid, to give the product (1.62 g, 32%) as a solid. ¹H NMR (300MHz, dimethylsulfoxide-d₆) 11.65 (brs, 1H), 8.55 (br s, 1H), 8.04 (d,1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d,2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m,4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd,2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).

Preparation of Compound 1 free base is also described in Example 5 ofU.S. application Ser. No. 12/787,682 (published as U.S. 2010/0305122)titled “Apoptosis-inducing agents for the treatment of cancer and immuneand autoimmune diseases,” the entire disclosure of which is incorporatedherein by reference. A solid can be prepared from the chromatographyeluate; for example, by using freeze-drying, precipitation, or rotaryevaporation techniques. The product of this process can be a solid thatis amorphous in character.

Salts and crystal forms of Compound 1 have been prepared as described inthe following examples.

Compound 1 Free Base Anhydrate PXRD Pattern A

The following two routes can prepare this crystalline form, where dryingat ambient conditions involves leaving the solid material at roomtemperature and exposed to air overnight. For example, solvent can beallowed to evaporate.

Example 1

Compound 1 free base dichloromethane solvate having pattern E (seebelow) was dried at ambient conditions.

Example 2

Compound 1 free base ethyl acetate solvate having pattern F (see below)was dried at ambient conditions.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 1and Table 1, respectively.

TABLE 1 Peak Listing for Compound 1 Free Base Anhydrate Pattern A PeakPosition (° 2θ) 6.3 7.1 9.0 9.5 12.5 14.5 14.7 15.9 16.9 18.9

Compound 1 Free Base Anhydrate PXRD Pattern B Example 3

Compound 1 free base acetonitrile solvate pattern H was dried at ambientconditions.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 2and Table 2, respectively.

TABLE 2 Peak Listing for Compound 1 Free Base Anhydrate Pattern B PeakPosition (° 2θ) 5.8 7.7 8.3 9.9 13.0 13.3 14.2 15.3 16.6 17.9 18.3 19.820.7 21.2 21.9 22.5 23.6 24.1

Compound 1 Free Base Hydrate PXRD Pattern C

The free base hydrate, characterized by Pattern C, can be prepared inthree ways.

Example 4

Compound 1 free base methanol solvate was dried at ambient conditions.

Example 5

Compound 1 free base ethanol solvate was dried at ambient conditions.

Example 6

Compound 1 free base 2-propanol solvate was dried at ambient conditions.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 3and Table 3, respectively.

TABLE 3 Peak Listing for Compound 1 Free Base Hydrate Pattern C PeakPosition (° 2θ) 5.8 7.6 7.9 10.7 11.7 14.0 15.3 15.8 17.4 18.3 19.9 20.420.7 22.5 24.9 25.8 26.7

Compound 1 Free Base Hydrate PXRD Pattern D Example 7

Compound 1 free base ethyl acetate solvate pattern G was dried atambient conditions.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 4and Table 4, respectively.

TABLE 4 Peak Listing for Compound 1 Free Base Hydrate Pattern D PeakPosition (° 2θ) 3.3 6.4 7.1 7.3 10.1 11.4 13.2 14.4 14.6 15.1 15.8 16.217.2 17.6 18.0 18.6 19.0 19.5 19.8 20.2 20.7 21.0 22.5 23.0 26.0 28.929.2

Compound 1 Free Base Dichloromethane Solvate PXRD Pattern E Example 8

Compound 1 free base solid was suspended in dichloromethane at ambienttemperatures to reach its solubility. After equilibrating, the solidswere isolated at ambient temperature.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 5and Table 5A, respectively. Crystallographic information is listed inTable 5B.

TABLE 5A Calculated PXRD Peak Listing for Compound 1 Free BaseDichloromethane Solvate Pattern E Peak Position (° 2θ) 5.9 7.1 9.6 10.010.7 11.1 13.2 14.8 18.2

TABLE 5B Structural Information for Compound 1 Free Base DichloromethaneSolvate Single Crystal Compound 1 Free Base Crystal Form DichloromethaneSolvate Lattice Type Monoclinic Space Group P21/n a (Å) 13.873 b (Å)12.349 c (Å) 29.996 α (°) 90.00 β (°) 92.259 γ (°) 90.00 Volume (Å³)5134.85 Z 4

Compound 1 Free Base Ethyl Acetate Solvate PXRD Pattern F Example 9

Compound 1 free base solid was suspended in ethyl acetate at ambienttemperatures to reach its solubility. After equilibrating, the solidswere isolated at ambient temperature.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 6and Table 6, respectively.

TABLE 6 PXRD Peak Listing for Compound 1 Free Base Ethyl Acetate SolvatePattern F Peak Position (° 2θ) 5.8 7.1 9.5 9.9 10.6 11.6 13.1 13.8 14.816.0 17.9 20.2 21.2 23.2 24.4 26.4

Compound 1 Free Base Ethyl Acetate Solvate PXRD Pattern G Example 10

Compound 1 free base solid was suspended in ethyl acetate saturated withwater at ambient temperatures to reach its solubility. Afterequilibrating, the solids were isolated at ambient temperature.

Powder X-ray diffraction pattern and peak listing shown in FIG. 7 andTable 7, respectively.

TABLE 7 PXRD Peak Listing for Compound 1 Free Base Ethyl Acetate SolvatePattern G Peak Position (° 2θ) 3.3 6.5 7.0 7.3 9.2 9.7 11.2 11.4 11.912.9 14.4 14.9 15.8 16.2 17.2 17.4 17.8 18.5 18.9 19.4 20.1 20.7 20.922.0 22.7 23.4 23.8 24.7 25.9 27.0 28.9

Compound 1 Free Base Acetonitrile Solvate PXRD Pattern H Example 11

Compound 1 free base solid was suspended in acetonitrile at ambienttemperatures to reach its solubility. After equilibrating, the solidswere isolated at ambient temperature.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 8and Table 8A, respectively. Crystallographic information is listed inTable 8B.

TABLE 8A Calculated PXRD Peak Listing for Compound 1 Free BaseAcetonitrile Solvate Pattern H Peak Position (° 2θ) 5.8 7.4 7.6 10.213.0 13.6 14.9 16.4 17.0 17.5 18.2 19.4 19.7 20.4 21.0 21.2 21.8 22.422.9 24.2 24.3 26.1 29.2

TABLE 8B Structural information for Compound 1 Free Base AcetonitrileSolvate H Single Crystal Compound 1 Free Base Crystal Form AcetonitrileSolvate A Lattice Type Triclinic Space Group P1 a (Å) 12.836 b (Å)13.144 c (Å) 15.411 α (°) 92.746 β (°) 95.941 γ (°) 113.833 Volume (Å³)2354.06 Z 2

Compound 1 Free Base Acetonitrile Solvate PXRD Pattern I Example 12

To a solution of2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid (16 g, 28 mmol) and3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide(8.83 g, 28 mmol) in DCM (300 mL) was added EDCI (10.74 g, 56 mmol) andDMAP (6.85 g, 56 mmol). The mixture was stirred at r.t. overnight. LC/MSshowed the expected product as a single peak. The mixture was dilutedwith DCM (500 ml) and washed with aq. NaHCO3, water, brine and driedover Na2SO4. The residue after evaporation of solvent was dissolved inDCM and loaded on a column and eluted with 30% ethyl acetate in DCMfollowed by 1 to 2% MeOH in DCM to give 24.5 g pure product (95% purity)which was dissolved in DMSO and MeOH (1:1) and TFA (2 eq) and loaded ona 330 g C18 column (6 g a time) to give 13.5 g pure (>99.7% purity)product (55% yield). The API was extracted using dichloromethane andthen, the solvent was removed using rotary evaporator. The resultingsolid was suspended in acetonitrile at ambient temperatures to reach itssolubility. After equilibrating, the solids were isolated at ambienttemperature.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 9and Table 9, respectively.

TABLE 9 PXRD Peak Listing for Compound 1 Free Base Acetonitrile SolvatePattern I Peak Position (° 2θ) 6.4 6.9 7.7 8.8 9.4 11.1 12.3 12.8 16.517.0 17.4 18.3 18.6 19.0 19.2 20.3 21.6 22.3 22.9 23.7

Compound 1 Free Base Acetone Solvate PXRD Pattern J Example 13

Compound 1 free base solid was suspended in acetone at ambienttemperatures to reach its solubility. After equilibrating, the solidswere isolated at ambient temperature.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 10and Table 10, respectively.

TABLE 10 PXRD Peak Listing for Compound 1 Free Base Acetone SolvatePattern J Peak Position (° 2θ) 6.0 6.8 8.0 9.0 9.7 11.2 11.9 12.6 14.715.0 15.2 15.8 16.4 16.6 17.6 17.8 17.9 18.7 20.2 20.8 21.6 22.2 22.623.3 23.8 24.0 24.4 26.8 27.1 28.0 28.2

Compound 1 Hydrochloride PXRD Pattern K Example 14

Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mLof acetonitrile. Hydrochloric acid (1M, 25 μL) was added to thesuspension while stirring (molar ratio of Compound 1:acid=1:1.4).Compound 1 quickly reacted with hydrochloric acid and formed a clearsolution. Yellowish solids, which later crystallized from the solution,were confirmed to be Compound 1 hydrochloride in a 1:1 stoichiometricratio of free base to HCl.

Powder X-ray diffraction pattern and peak listing can be seen in FIG.11, and Table 11A, respectively. Crystallographic information is listedin Table 11B.

TABLE 11A Calculated PXRD Peak Listing of Compound 1 HydrochloridePattern K Peak Position (° 2θ) 5.1 5.9 7.7 9.9 10.2 10.8 13.6 14.0 15.415.9 16.2 17.6 18.3 18.7 19.7 19.9 20.1 20.4 20.7 20.9 22.9 26.2

TABLE 11B Structural information for Compound 1 Hydrochloride Compound 1Crystal Form Hydrochloride Lattice Type Triclinic Space Group P1 a (Å)10.804 b (Å) 12.372 c (Å) 19.333 α (°) 76.540 β (°) 87.159 γ (°) 70.074Volume (Å³) 2361.5 Z 2

Compound 1 Hydrochloride Hydrate PXRD Pattern L Example 15

Compound 1 hydrochloride solid (having pattern K) was exposed to the airunder ambient conditions, and was confirmed to be Compound 1hydrochloride hydrate.

Powder X-ray diffraction pattern and peak listing can be seen in FIG.12, and Table 12, respectively.

TABLE 12 PXRD Peak Listing for Compound 1 Hydrochloride Hydrate PatternL Peak Position (° 2θ) 4.6 8.7 9.6 9.9 12.3 14.9 15.7 17.6 18.1 18.419.3 19.6 21.0 23.3 23.9 24.8 26.5 27.2 27.4 29.0 30.1

Compound 1 Sulfate PXRD Pattern M Example 16

Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mLof 2-propanol at 70° C. Sulfuric acid (1M, 25 μL) was added to thesuspension while stirring (molar ratio of Compound 1:acid=1:1.4).Compound 1 quickly dissolved by reacting with sulfuric acid. Yellowishsolids crystallized from the solution immediately after the dissolutionoccurred. The crystalline solid was confirmed to be Compound 1 sulfatewith a stoichiometry of 1:1 using ion chromatography.

Powder X-ray diffraction pattern and peak listing can be seen in FIG.13, and Table 13, respectively.

TABLE 13 PXRD Peak Listing for Compound 1 Sulfate Pattern M PeakPosition (° 2θ) 4.8 7.7 8.3 9.7 10.2 12.0 12.6 14.5 15.4 17.4 17.9 18.419.1 19.5 21.0 22.4 23.3 23.9 25.1 26.8

Compound 1 Free Base THF Solvate PXRD Pattern N Example 17

Compound 1 free base solid was suspended in tetrahydrofuran (THF) atambient temperatures to reach its solubility. After equilibrating, thesolids were isolated at ambient temperature.

Powder X-ray diffraction pattern and peak listing are shown in FIG. 14and Table 14, respectively.

TABLE 14 PXRD Peak Listing for Compound 1 Free Base THF Solvate PatternN Peak Position (° 2θ) 4.0 4.6 8.0 8.5 9.4 14.6 17.1 17.4 17.8 18.1 19.219.5 20.1 20.4 20.5 21.7

PXRD data were collected using a G3000 diffractometer (Inel Corp.,Artenay, France) equipped with a curved position-sensitive detector andparallel-beam optics. The diffractometer was operated with a copperanode tube (1.5 kW fine focus) at 40 kV and 30 mA. An incident-beamgermanium monochromator provided monochromatic radiation Cu-K_(α)radiation, which has a wavelength of 1.54178 Å. The diffractometer wascalibrated using the attenuated direct beam at one-degree intervals.Calibration was checked using a silicon powder line position referencestandard (NIST 640c). The instrument was computer-controlled usingSymphonix software (Inel Corp., Artenay, France) and the data wereanalyzed using Jade software (version 6.5, Materials Data, Inc.,Livermore, Calif.). The sample was loaded onto an aluminum sample holderand leveled with a glass slide. PXRD peak position measurements aretypically ±0.2 degrees two-theta (° 20).

In some embodiments, the percent crystallinity of any of the salt orcrystalline forms of Compound 1 described herein can vary with respectto the total amount of Compound 1. In particular, certain embodimentsprovide for the percent crystallinity of a salt or crystalline form ofCompound 1 being at least 10%, at least 20%, at least 30%, at least 40%,at least 50%, at least, 60%, at least 70%, at least 80%, at least 90%,at least 95%, or at least 99%. In some embodiments, the percentcrystallinity can be substantially 100%, where substantially 100%indicates that the entire amount of Compound 1 appears to be crystallineas best can be determined using methods known in the art. Accordingly,pharmaceutical compositions and therapeutically effective amounts ofCompound 1 can include amounts that vary in crystallinity. These includeinstances where Compound 1 is used as API in various formulations andsolid forms, including where an amount of Compound 1 in a solid form issubsequently dissolved, partially dissolved, or suspended or dispersedin a liquid.

As noted, in some embodiments API compositions are provided thatcomprise Compound 1, wherein at least a portion of the Compound 1 in theAPI composition is in one of the salt or crystalline forms. For example,an API composition containing Compound 1 has at least 10%, at least 20%,at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 95% or at least 99% of the compound ofthe composition in one of the salt or crystalline forms. In someembodiments, essentially 100% of the Compound 1 of an API formulation isin a salt or crystalline form as described herein.

Any of the crystalline forms of Compound 1, including salts and solvatedforms, can be useful as an active pharmaceutical ingredient (API) forpreparation of pharmaceutical compositions. However, solvent-free formsare generally preferred for this purpose. A hydrate is consideredsolvent-free for this purpose. Solvated forms can be, as indicatedabove, useful as process intermediates in preparation of solvent-freeforms. Compound 1 salts and crystalline forms can be used in preparationof pharmaceutical compositions suitable for various routes ofadministration, including oral, to a subject in need thereof. Thus, insome embodiments, a pharmaceutical composition is provided, comprising acrystalline form of Compound 1 and one or more pharmaceuticallyacceptable excipients. Such compositions can be prepared using variousknown processes of pharmacy.

In some embodiments, the salt or crystalline form of Compound 1 includesthose of Compound 1 free base anhydrate having PXRD pattern A, Compound1 free base anhydrate having PXRD pattern B, Compound 1 free basehydrate having PXRD pattern C, Compound 1 free base hydrate having PXRDpattern D, Compound 1 free base dichloromethane solvate having patternE, Compound 1 free base ethyl acetate solvate having PXRD pattern F,Compound 1 free base ethyl acetate solvate having PXRD pattern G,Compound 1 free base acetonitrile solvate having PXRD pattern H,Compound 1 free base acetonitrile solvate having PXRD pattern I,Compound 1 free base acetone solvate having PXRD pattern J, Compound 1hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydratehaving PXRD pattern L, Compound 1 sulfate having PXRD pattern M, andCompound 1 free base tetrahydrofuran (THF) solvate having PXRD patternN, each having the respective powder X-ray diffraction patterns asdescribed herein.

According to any of these embodiments, the composition can bedeliverable, for example, by the oral route. Other routes ofadministration include without limitation parenteral, sublingual,buccal, intranasal, pulmonary, topical, transdermal, intradermal,ocular, otic, rectal, vaginal, intragastric, intracranial, intrasynovialand intra-articular routes.

Where it is desired to provide Compound 1 free base or salt in solutionform, for example in a liquid formulation for oral or parenteraladministration, the Compound 1 free base or salt will not, of course, bepresent in such a formulation in crystalline form; indeed, the presenceof crystals is generally undesired in such a formulation. However, acrystalline form of Compound 1 free base can nonetheless be important asAPI in a process for preparing such a formulation. Thus, the presentdisclosure further provides a process for preparing a pharmaceuticalsolution composition of Compound 1 comprising dissolving a crystallinesalt or a crystalline form of Compound 1 free base in a pharmaceuticallyacceptable solvent or mixture of solvents. Even where the desiredformulation is one containing Compound 1 free base in amorphous form,for example a solid melt formulation, a crystalline form of Compound 1free base can still be useful as API in a process for preparing such aformulation.

As API, a crystalline form of Compound 1 free base or mixtures thereofcan have advantages over an amorphous form. For example, purification ofAPI to the high degree of purity required by most regulatory authoritiescan be more efficient and therefore cost less where the API is incrystalline form as opposed to amorphous form. Physical and chemicalstability, and therefore shelf-life of the API solid, can also be betterfor crystalline than amorphous forms. Ease of handling can be improvedover the amorphous form, which can be oily or sticky. Drying can be morestraightforward and more easily controlled in the case of thecrystalline material, which can have a well-defined drying ordesolvation temperature, than in the case of the amorphous material,which can have greater affinity for organic solvents and no well-defineddrying temperature. Downstream processing using crystalline API canfurther permit enhanced process control. In preparing a liquidformulation, for example a solution in a lipid carrier, crystallineCompound 1 can dissolve faster and can have a reduced tendency to form agel during dissolution. These advantages are illustrative andnon-limiting.

Pharmaceutical compositions comprising crystalline Compound 1 free base,or prepared using crystalline Compound 1 free base or salts of Compound1 as API, contain Compound 1 in an amount that can be therapeuticallyeffective when the composition is administered to a subject in needthereof according to an appropriate regimen. Dosage amounts areexpressed herein as free base equivalent amounts unless the contextrequires otherwise. Typically, a unit dose (the amount administered at asingle time), which can be administered at an appropriate frequency,e.g., twice daily to once weekly, is about 10 to about 1,000 mg. Wherefrequency of administration is once daily (q.d.), unit dose and dailydose are the same. Illustratively, the unit dose of Compound 1 in acomposition of the invention can be about 25 to about 1,000 mg, moretypically about 50 to about 500 mg, for example about 50, about 100,about 150, about 200, about 250, about 300, about 350, about 400, about450 or about 500 mg. Where the composition is prepared as a discretedosage form such as a tablet or capsule, a unit dose can be deliverablein a single dosage form or a small plurality of dosage forms, mosttypically 1 to about 10 dosage forms.

The higher the unit dose, the more desirable it becomes to selectexcipients that permit a relatively high loading of API (in this caseCompound 1 free base or salt) in the formulation. Typically, theconcentration of Compound 1 in a formulation prepared according to thepresent disclosure is at least about 1%, e.g., about 1% to about 25%, byweight, but lower and higher concentrations can be acceptable orachievable in specific cases. Illustratively, the Compound 1 free baseequivalent concentration in various embodiments is at least about 2%,e.g., about 2% to about 20%, by weight, for example about 5%, about 10%or about 15%, by weight of the formulation.

A composition prepared according to the invention comprises, in additionto the API, one or more pharmaceutically acceptable excipients. If thecomposition is to be prepared in solid form for oral administration, forexample as a tablet or capsule, it typically includes at least one ormore solid diluents and one or more solid disintegrants. Optionally, theexcipients further include one or more binding agents, wetting agentsand/or antifrictional agents (lubricants, anti-adherents and/orglidants). Many excipients have two or more functions in apharmaceutical composition. Characterization herein of a particularexcipient as having a certain function, e.g., diluent, disintegrant,binding agent, etc., should not be read as limiting to that function.Further information on excipients can be found in standard referenceworks such as Handbook of Pharmaceutical Excipients, 3rd ed. (Kibbe, ed.(2000), Washington: American Pharmaceutical Association).

Suitable diluents illustratively include, either individually or incombination, lactose, including anhydrous lactose and lactosemonohydrate; lactitol; maltitol; mannitol; sorbitol; xylitol; dextroseand dextrose monohydrate; fructose; sucrose and sucrose-based diluentssuch as compressible sugar, confectioner's sugar and sugar spheres;maltose; inositol; hydrolyzed cereal solids; starches (e.g., cornstarch, wheat starch, rice starch, potato starch, tapioca starch, etc.),starch components such as amylose and dextrates, and modified orprocessed starches such as pregelatinized starch; dextrins; cellulosesincluding powdered cellulose, microcrystalline cellulose, silicifiedmicrocrystalline cellulose, food grade sources of α- and amorphouscellulose and powdered cellulose, and cellulose acetate; calcium saltsincluding calcium carbonate, tribasic calcium phosphate, dibasic calciumphosphate dihydrate, monobasic calcium sulfate monohydrate, calciumsulfate and granular calcium lactate trihydrate; magnesium carbonate;magnesium oxide; bentonite; kaolin; sodium chloride; and the like. Suchdiluents, if present, typically constitute in total about 5% to about95%, for example about 20% to about 90%, or about 50% to about 85%, byweight of the composition. The diluent or diluents selected preferablyexhibit suitable flow properties and, where tablets are desired,compressibility.

Microcrystalline cellulose and silicified microcrystalline cellulose areparticularly useful diluents, and are optionally used in combinationwith a water-soluble diluent such as mannitol. Illustratively, asuitable weight ratio of microcrystalline cellulose or silicifiedmicrocrystalline cellulose to mannitol is about 10:1 to about 1:1, butratios outside this range can be useful in particular circumstances.

Suitable disintegrants include, either individually or in combination,starches including pregelatinized starch and sodium starch glycolate;clays; magnesium aluminum silicate; cellulose-based disintegrants suchas powdered cellulose, microcrystalline cellulose, methylcellulose,low-substituted hydroxypropylcellulose, carmellose, carmellose calcium,carmellose sodium and croscarmellose sodium; alginates; povidone;crospovidone; polacrilin potassium; gums such as agar, guar, locustbean, karaya, pectin and tragacanth gums; colloidal silicon dioxide; andthe like. One or more disintegrants, if present, typically constitute intotal about 0.2% to about 30%, for example about 0.5% to about 20%, orabout 1% to about 10%, by weight of the composition.

Sodium starch glycolate is a particularly useful disintegrant, andtypically constitutes in total about 1% to about 20%, for example about2% to about 15%, or about 5% to about 10%, by weight of the composition.

Binding agents or adhesives are useful excipients, particularly wherethe composition is in the form of a tablet. Such binding agents andadhesives should impart sufficient cohesion to the blend being tabletedto allow for normal processing operations such as sizing, lubrication,compression and packaging, but still allow the tablet to disintegrateand the composition to be absorbed upon ingestion. Suitable bindingagents and adhesives include, either individually or in combination,acacia; tragacanth; glucose; polydextrose; starch includingpregelatinized starch; gelatin; modified celluloses includingmethylcellulose, carmellose sodium, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose, hydroxyethylcellulose and ethylcellulose;dextrins including maltodextrin; zein; alginic acid and salts of alginicacid, for example sodium alginate; magnesium aluminum silicate;bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum;polysaccharide acids; polyvinylpyrrolidone (povidone or PVP), forexample povidone K-15, K-30 and K-29/32; polyacrylic acids (carbomers);polymethacrylates; and the like. One or more binding agents and/oradhesives, if present, typically constitute in total about 0.5% to about25%, for example about 1% to about 15%, or about 1.5% to about 10%, byweight of the composition.

Povidone and hydroxypropylcellulose, either individually or incombination, are particularly useful binding agents for tabletformulations, and, if present, typically constitute about 0.5% to about15%, for example about 1% to about 10%, or about 2% to about 8%, byweight of the composition.

Wetting agents, if present, are normally selected to maintain the drugin close association with water, a condition that can improvebioavailability of the composition. Non-limiting examples of surfactantsthat can be used as wetting agents include, either individually or incombination, quaternary ammonium compounds, for example benzalkoniumchloride, benzethonium chloride and cetylpyridinium chloride; dioctylsodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, for examplenonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethyleneand polyoxypropylene block copolymers); polyoxyethylene fatty acidglycerides and oils, for example polyoxyethylene (8) caprylic/capricmono- and diglycerides, polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10,oleth-20, steareth-2, steareth-10, steareth-20, steareth-100 andpolyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acidesters, for example polyoxyethylene (20) stearate, polyoxyethylene (40)stearate and polyoxyethylene (100) stearate; sorbitan esters, forexample sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate; polyoxyethylene sorbitanesters, for example polysorbate 20 and polysorbate 80; propylene glycolfatty acid esters, for example propylene glycol laurate; sodium laurylsulfate; fatty acids and salts thereof, for example oleic acid, sodiumoleate and triethanolamine oleate; glyceryl fatty acid esters, forexample glyceryl monooleate, glyceryl monostearate and glycerylpalmitostearate; tyloxapol; and the like. One or more wetting agents, ifpresent, typically constitute in total about 0.1% to about 15%, forexample about 0.2% to about 10%, or about 0.5% to about 7%, by weight ofthe composition.

Nonionic surfactants, more particularly poloxamers, are examples ofwetting agents that can be useful herein. Illustratively, a poloxamersuch as Pluronic™ F127, if present, can constitute about 0.1% to about10%, for example about 0.2% to about 7%, or about 0.5% to about 5%, byweight of the composition.

Lubricants reduce friction between a tableting mixture and tabletingequipment during compression of tablet formulations. Suitable lubricantsinclude, either individually or in combination, glyceryl behenate;stearic acid and salts thereof, including magnesium, calcium and sodiumstearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc;waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearylfumarate; PEGs (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinylalcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate;and the like. One or more lubricants, if present, typically constitutein total about 0.05% to about 10%, for example about 0.1% to about 5%,or about 0.2% to about 2%, by weight of the composition. Sodium stearylfumarate is a particularly useful lubricant.

Anti-adherents reduce sticking of a tablet formulation to equipmentsurfaces. Suitable anti-adherents include, either individually or incombination, talc, colloidal silicon dioxide, starch, DL-leucine, sodiumlauryl sulfate and metallic stearates. One or more anti-adherents, ifpresent, typically constitute in total about 0.05% to about 10%, forexample about 0.1% to about 7%, or about 0.2% to about 5%, by weight ofthe composition. Colloidal silicon dioxide is a particularly usefulanti-adherent.

Glidants improve flow properties and reduce static in a tabletingmixture. Suitable glidants include, either individually or incombination, colloidal silicon dioxide, starch, powdered cellulose,sodium lauryl sulfate, magnesium trisilicate and metallic stearates. Oneor more glidants, if present, typically constitute in total about 0.05%to about 10%, for example about 0.1% to about 7%, or about 0.2% to about5%, by weight of the composition. Colloidal silicon dioxide is aparticularly useful glidant.

Other excipients such as buffering agents, stabilizers, antioxidants,antimicrobials, colorants, flavors and sweeteners are known in thepharmaceutical art and can be used in compositions of the presentinvention. Tablets can be uncoated or can comprise a core that iscoated, for example with a nonfunctional film or a release-modifying orenteric coating. Capsules can have hard or soft shells comprising, forexample, gelatin (in the form of hard gelatin capsules or soft elasticgelatin capsules), starch, carrageenan and/or HPMC, optionally togetherwith one or more plasticizers.

A solid orally deliverable composition of the present invention is notlimited by any process used to prepare it. Any suitable process ofpharmacy can be used, including dry blending with or without directcompression, and wet or dry granulation.

If the composition is to be prepared in liquid (including encapsulatedliquid) form, the API (e.g., crystalline Compound 1 free base or salt)can be, for example, dissolved in a suitable carrier, typically onecomprising a lipid solvent for the API. The higher the unit dose, themore desirable it becomes to select a carrier that permits a relativelyhigh concentration of the drug in solution therein. Typically, the freebase equivalent concentration of API in the carrier is at least about 10mg/ml, e.g., about 10 to about 500 mg/ml, but lower and higherconcentrations can be acceptable or achievable in specific cases.Illustratively, the drug concentration in various embodiments is atleast about 10 mg/ml, e.g., about 10 to about 250 mg/ml, or at leastabout 20 mg/ml, e.g., about 20 to about 200 mg/ml, for example about 20,about 25, about 30, about 40, about 50, about 75, about 100 or about 150mg/ml.

The carrier can be substantially non-aqueous, i.e., having no water, orhaving an amount of water that is small enough to be, in practicalterms, essentially non-deleterious to performance or properties of thecomposition. Typically, the carrier comprises zero to less than about 5%by weight water. It will be understood that certain ingredients usefulherein can bind small amounts of water on or within their molecules orsupramolecular structures; such bound water if present does not affectthe “substantially non-aqueous” character of a carrier as definedherein.

In some embodiments, the carrier comprises one or more glyceridematerials. Suitable glyceride materials include, without limitation,medium to long chain mono-, di- and triglycerides. The term “mediumchain” herein refers to hydrocarbyl chains individually having no lessthan about 6 and less than about 12 carbon atoms, including for exampleC₈ to C₁₀ chains. Thus glyceride materials comprising caprylyl andcapryl chains, e.g., caprylic/capric mono-, di- and/or triglycerides,are examples of “medium chain” glyceride materials herein. The term“long chain” herein refers to hydrocarbyl chains individually having atleast about 12, for example about 12 to about 18, carbon atoms,including for example lauryl, myristyl, cetyl, stearyl, oleyl, linoleyland linolenyl chains. Medium to long chain hydrocarbyl groups in theglyceride materials can be saturated, mono- or polyunsaturated.

In one embodiment the carrier comprises a medium chain and/or a longchain triglyceride material. A suitable example of a medium chaintriglyceride material is a caprylic/capric triglyceride product such as,for example, Captex 355 EP™ of Abitec Corp. and products substantiallyequivalent thereto. Suitable examples of long chain triglyceridesinclude any pharmaceutically acceptable vegetable oil, for examplecanola, coconut, corn, cottonseed, flaxseed, olive, palm, peanut,safflower, sesame, soy and sunflower oils, and mixtures of such oils.Oils of animal, particularly marine animal, origin can also be used,including for example fish oil.

In some embodiments the carrier comprises a phospholipid and apharmaceutically acceptable solubilizing agent for the phospholipid. Itwill be understood that reference in the singular to a (or the)phospholipid, solubilizing agent or other formulation ingredient hereinincludes the plural; thus combinations, for example mixtures, of morethan one phospholipid, or more than one solubilizing agent, areexpressly contemplated herein. The solubilizing agent, or thecombination of solubilizing agent and phospholipid, also solubilizes thedrug, although other carrier ingredients, such as a surfactant or analcohol such as ethanol, optionally present in the carrier can in somecircumstances provide enhanced solubilization of the drug.

Any pharmaceutically acceptable phospholipid or mixture of phospholipidscan be used. In general such phospholipids are phosphoric acid estersthat yield on hydrolysis phosphoric acid, fatty acid(s), an alcohol anda nitrogenous base. Pharmaceutically acceptable phospholipids caninclude without limitation phosphatidylcholines, phosphatidylserines andphosphatidylethanolamines. In one embodiment the composition comprisesphosphatidylcholine, derived for example from natural lecithin. Anysource of lecithin can be used, including animal sources such as eggyolk, but plant sources are generally preferred. Soy is a particularlyrich source of lecithin that can provide phosphatidylcholine for use inthe present invention.

Illustratively, a suitable amount of phospholipid is about 15% to about75%, for example about 30% to about 60%, by weight of the carrier,although greater and lesser amounts can be useful in particularsituations.

Ingredients useful as components of the solubilizing agent are notparticularly limited and will depend to some extent on the desiredconcentration of drug and of phospholipid. In one embodiment, thesolubilizing agent comprises one or more glycols and/or one or moreglyceride materials.

Suitable glycols include propylene glycol and polyethylene glycols(PEGs) having molecular weight of about 200 to about 1,000 g/mol, e.g.,PEG-400, which has an average molecular weight of about 400 g/mol. Suchglycols can provide relatively high solubility of the drug; however thepotential for oxidative degradation of the drug can be increased when insolution in a carrier comprising such glycols, for example because ofthe tendency of glycols to produce superoxides, peroxides and/or freehydroxyl radicals. The higher the glycol content of the carrier, thegreater may be the tendency for degradation of a chemically unstabledrug. In one embodiment, therefore, one or more glycols are present in atotal glycol amount of at least about 1% but less than about 50%, forexample less than about 30%, less than about 20%, less than about 15% orless than about 10% by weight of the carrier. In another embodiment, thecarrier comprises substantially no glycol.

Suitable glyceride materials for use together with a phospholipidinclude, without limitation, those mentioned above. Where one or moreglyceride materials are present as a major component of the solubilizingagent, a suitable total amount of glycerides is an amount effective tosolubilize the phospholipid and, in combination with other components ofthe carrier, effective to maintain the drug and antioxidant in solution.For example, glyceride materials such as medium chain and/or long chaintriglycerides can be present in a total glyceride amount of about 5% toabout 70%, for example about 15% to about 60% or about 25% to about 50%,by weight of the carrier.

Additional solubilizing agents that are other than glycols or glyceridematerials can be included if desired. Such agents, for exampleN-substituted amide solvents such as dimethylformamide (DMF) andN,N-dimethylacetamide (DMA), can, in specific cases, assist in raisingthe limit of solubility of the drug in the carrier, thereby permittingincreased drug loading. However, N-substituted amides including DMF andDMA can present regulatory and/or toxicological issues that restrict theamount of such solvents that can be used in a formulation. Furthermore,the carriers useful herein generally provide adequate solubility ofsmall-molecule drugs of interest herein without such additional agents.

Even when a sufficient amount of a glycol or glyceride material ispresent to solubilize the phospholipid, the resulting carrier solutionand/or the drug-carrier system may be rather viscous and difficult orinconvenient to handle. In such cases it may be found desirable toinclude in the carrier a viscosity reducing agent in an amount effectiveto provide acceptably low viscosity. An example of such an agent is analcohol, more particularly ethanol, which is preferably introduced in aform that is substantially free of water, for example 99% ethanol,dehydrated alcohol USP or absolute ethanol. Excessively highconcentrations of ethanol should, however, generally be avoided. This isparticularly true where, for example, the drug-carrier system is to beadministered in a gelatin capsule, because of the tendency of highethanol concentrations to result in mechanical failure of the capsule.In general, suitable amounts of ethanol are 0% to about 25%, for exampleabout 1% to about 20% or about 3% to about 15%, by weight of thecarrier.

Optionally, the carrier further comprises a pharmaceutically acceptablenon-phospholipid surfactant. One of skill in the art will be able toselect a suitable surfactant for use in a composition of the invention.Illustratively, a surfactant such as polysorbate 80 can be included inan amount of 0% to about 5%, for example 0% to about 2% or 0% to about1%, by weight of the carrier.

Conveniently, pre-blended products are available containing a suitablephospholipid +solubilizing agent combination for use in compositions ofthe present invention. Pre-blended phospholipid +solubilizing agentproducts can be advantageous in improving ease of preparation of thepresent compositions.

An illustrative example of a pre-blended phospholipid +solubilizingagent product is Phosal 50 PG™, available from Phospholipid GmbH,Germany, which comprises, by weight, not less than 50%phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 35%propylene glycol, about 3% mono- and diglycerides from sunflower oil,about 2% soy fatty acids, about 2% ethanol, and about 0.2% ascorbylpalmitate.

Another illustrative example is Phosal 53 MCT™, also available fromPhospholipid GmbH, which contains, by weight, not less than 53%phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 29%medium chain triglycerides, 3-6% (typically about 5%) ethanol, about 3%mono- and diglycerides from sunflower oil, about 2% oleic acid, andabout 0.2% ascorbyl palmitate (reference composition). A product havingthe above or substantially equivalent composition, whether sold underthe Phosal 53 MCT™ brand or otherwise, is generically referred to hereinas “phosphatidylcholine +medium chain triglycerides 53/29”. A producthaving “substantially equivalent composition” in the present contextmeans having a composition sufficiently similar to the referencecomposition in its ingredient list and relative amounts of ingredientsto exhibit no practical difference in properties with respect toutilization of the product herein.

Yet another illustrative example is Phosal 50 SA+™, also available fromPhospholipid GmbH, which contains, by weight, not less than 50%phosphatidylcholine and not more than 6% lysophosphatidylcholine in asolubilizing system comprising safflower oil and other ingredients.

The phosphatidylcholine component of each of these pre-blended productscan be derived from soy lecithin. Products of substantially equivalentcomposition may be obtainable from other suppliers.

A pre-blended product such as Phosal 50 PG™, Phosal 53 MCT™ or Phosal 50SA+™ can, in some embodiments, constitute substantially the entirecarrier system. In other embodiments, additional ingredients arepresent, for example ethanol (additional to any that may be present inthe pre-blended product), non-phospholipid surfactant such aspolysorbate 80, polyethylene glycol and/or other ingredients. Suchadditional ingredients, if present, are typically included in only minoramounts. Illustratively, phosphatidylcholine +medium chain triglycerides53/29 can be included in the carrier in an amount of about 50% to 100%,for example about 80% to 100%, by weight of the carrier.

Without being bound by theory, it is believed that the therapeuticefficacy of Compound 1 is due at least in part to its ability to bind toa Bcl-2 family protein such as Bcl-2, Bcl-X_(L) or Bcl-w in a way thatinhibits the anti-apoptotic action of the protein, for example byoccupying the BH3 binding groove of the protein.

In still further embodiments of the invention, there is provided amethod for treating a disease characterized by apoptotic dysfunctionand/or overexpression of an anti-apoptotic Bcl-2 family protein,comprising administering to a subject having the disease atherapeutically effective amount of crystalline Compound 1 free base ora pharmaceutical composition comprising a salt or crystalline form ofCompound 1 free base and one or more pharmaceutically acceptableexcipients.

In still further embodiments of the invention, there is provided amethod for treating a disease characterized by apoptotic dysfunctionand/or overexpression of an anti-apoptotic Bcl-2 family protein isprovided, where the method comprises preparing a solution or dispersionof a salt or crystalline form of Compound 1 described herein in apharmaceutically acceptable solvent or mixture of solvents, andadministering the resulting solution or dispersion in a therapeuticallyeffective amount to a subject having the disease.

The subject can be human or non-human (e.g., a farm, zoo, work orcompanion animal, or a laboratory animal used as a model) but in animportant embodiment the subject is a human patient in need of the drug,for example to treat a disease characterized by apoptotic dysfunctionand/or overexpression of an anti-apoptotic Bcl-2 family protein. A humansubject can be male or female and of any age, but is typically an adult.

The composition is normally administered in an amount providing atherapeutically effective daily dose of the drug. The term “daily dose”herein means the amount of drug administered per day, regardless of thefrequency of administration. For example, if the subject receives a unitdose of 150 mg twice daily, the daily dose is 300 mg. Use of the term“daily dose” will be understood not to imply that the specified dosageamount is necessarily administered once daily. However, in a particularembodiment the dosing frequency is once daily (q.d.), and the daily doseand unit dose are in this embodiment the same thing.

What constitutes a therapeutically effective dose depends on thebioavailability of the particular formulation, the subject (includingspecies and body weight of the subject), the disease (e.g., theparticular type of cancer) to be treated, the stage and/or severity ofthe disease, the individual subject's tolerance of the compound, whetherthe compound is administered in monotherapy or in combination with oneor more other drugs, e.g., other chemotherapeutics for treatment ofcancer, and other factors. Thus, the daily dose can vary within widemargins, for example from about 10 to about 1,000 mg. Greater or lesserdaily doses can be appropriate in specific situations. It will beunderstood that recitation herein of a “therapeutically effective” doseherein does not necessarily require that the drug be therapeuticallyeffective if only a single such dose is administered; typicallytherapeutic efficacy depends on the composition being administeredrepeatedly according to a regimen involving appropriate frequency andduration of administration. It is strongly preferred that, while thedaily dose selected is sufficient to provide benefit in terms oftreating the cancer, it should not be sufficient to provoke an adverseside-effect to an unacceptable or intolerable degree. A suitabletherapeutically effective dose can be selected by the physician ofordinary skill without undue experimentation based on the disclosureherein and on art cited herein, taking into account factors such asthose mentioned above. The physician may, for example, start a cancerpatient on a course of therapy with a relatively low daily dose andtitrate the dose upwards over a period of days or weeks, to reduce riskof adverse side-effects.

Illustratively, suitable doses of Compound 1 are generally about 25 toabout 1000 mg/day or about 50 to about 1000 mg/day, more typically about50 to about 500 mg/day or about 200 to about 400 mg/day, for exampleabout 50, about 100, about 150, about 200, about 250, about 300, about350, about 400, about 450, about 500, about 750 or about 1000 mg/day,administered at an average dosage interval of about 3 hours to about 7days, for example about 8 hours to about 3 days, or about 12 hours toabout 2 days. In most cases a once-daily (q.d.) administration regimenis suitable.

An “average dosage interval” herein is defined as a span of time, forexample one day or one week, divided by the number of unit dosesadministered over that span of time. For example, where a drug isadministered three times a day, around 8 am, around noon and around 6pm, the average dosage interval is 8 hours (a 24-hour time span dividedby 3). If the drug is formulated as a discrete dosage form such as atablet or capsule, a plurality (e.g., 2 to about 10) of dosage formsadministered at one time is considered a unit dose for the purpose ofdefining the average dosage interval.

Compositions prepared according to the present invention are suitablefor use in monotherapy or in combination therapy, for example with otherchemotherapeutics or with ionizing radiation. A particular advantage ofthe present invention is that it permits once-daily oral administration,a regimen which is convenient for the patient who is undergoingtreatment with other orally administered drugs on a once-daily regimen.Oral administration is easily accomplished by the patient him/herself orby a caregiver in the patient's home; it is also a convenient route ofadministration for patients in a hospital or residential care setting.

Combination therapies illustratively include administration of acomposition comprising (or prepared using as API) one or morecrystalline forms of Compound 1 (including crystalline salt forms)concomitantly with one or more of bortezomid, carboplatin, cisplatin,cyclophosphamide, dacarbazine, dexamethasone, docetaxel, doxorubicin,etoposide, fludarabine, hydroxydoxorubicin, irinotecan, paclitaxel,rapamycin, rituximab, vincristine and the like, for example with apolytherapy such as CHOP (cyclophosphamide +hydroxydoxorubicin+vincristine +prednisone), RCVP (rituximab +cyclophosphamide+vincristine +prednisone), R-CHOP (rituximab +CHOP) or DA-EPOCH-R(dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide,doxorubicin and rituximab).

A Compound 1 composition can be administered in combination therapy withone or more therapeutic agents that include, but are not limited to,angiogenesis inhibitors, antiproliferative agents, other apoptosispromoters (for example, Bcl-xL, Bcl-w and Bfl-1 inhibitors), activatorsof a death receptor pathway, BiTE (bi-specific T-cell engager)antibodies, dual variable domain binding proteins (DVDs), inhibitors ofapoptosis proteins (IAPB), microRNAs, mitogen-activated extracellularsignal-regulated kinase inhibitors, multivalent binding proteins,poly-ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors,small inhibitory ribonucleic acids (siRNAs), kinase inhibitors, receptortyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinaseinhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), antimitoticagents, alkylating agents, antimetabolites, intercalating antibiotics,platinum-containing chemotherapeutic agents, growth factor inhibitors,ionizing radiation, cell cycle inhibitors, enzymes, topoisomeraseinhibitors, biologic response modifiers, immunologicals, antibodies,hormonal therapies, retinoids, deltoids, plant alkaloids, proteasomeinhibitors, HSP-90 inhibitors, histone deacetylase (HDAC) inhibitors,purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors,ErbB2 receptor inhibitors, mTOR inhibitors as well as other antitumoragents.

Angiogenesis inhibitors include, but are not limited to, EGFRinhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1Rinhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrixmetalloproteinase 9 (MMP-9) inhibitors and thrombospondin analogs.

Examples of EGFR inhibitors include, but are not limited to, gefitinib,erlotinib, cetuximab, EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38(IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFR immunoliposomes andlapatinib.

Examples of PDGFR inhibitors include, but are not limited to, CP-673451and CP-868596.

Examples of VEGFR inhibitors include, but are not limited to,bevacizumab, sunitinib, sorafenib, CP-547632, axitinib, vandetanib,AEE788, AZD-2171, VEGF trap, vatalanib, pegaptanib, IM862, pazopanib,ABT-869 and angiozyme.

Bcl-2 family protein inhibitors other than Compound 1 include, but arenot limited to, ABT-263, AT-101 ((−)gossypol), Genasense™Bcl-2-targeting antisense oligonucleotide (G3139 or oblimersen),IPI-194, IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737), GX-070 (obatoclax) and the like.

Activators of a death receptor pathway include, but are not limited to,TRAIL, antibodies or other agents that target death receptors (e.g., DR4and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab),HGS-1029, LBY-135, PRO-1762 and trastuzumab.

Examples of thrombospondin analogs include, but are not limited to,TSP-1, ABT-510, ABT-567 and ABT-898.

Examples of aurora kinase inhibitors include, but are not limited to,VX-680, AZD-1152 and MLN-8054.

An example of a polo-like kinase inhibitor includes, but is not limitedto, BI-2536.

Examples of bcr-abl kinase inhibitors include, but are not limited to,imatinib and dasatinib.

Examples of platinum-containing agents include, but are not limited to,cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatinand satraplatin.

Examples of mTOR inhibitors include, but are not limited to, CCI-779,rapamycin, temsirolimus, everolimus, RAD001 and AP-23573.

Examples of HSP-90 inhibitors include, but are not limited to,geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010,17-AAG-nab, NCS-683664, efungumab, CNF-2024, PU3, PU24FCl, VER-49009,IPI-504, SNX-2112 and STA-9090.

Examples of HDAC inhibitors include, but are not limited to,suberoylanilide hydroxamic acid (SAHA), MS-275, valproic acid, TSA,LAQ-824, trapoxin and depsipeptide.

Examples of MEK inhibitors include, but are not limited to, PD-325901,ARRY-142886, ARRY-438162 and PD-98059.

Examples of CDK inhibitors include, but are not limited to,flavopyridol, MCS-5A, CVT-2584, seliciclib ZK-304709, PHA-690509,BMI-1040, GPC-286199, BMS-387032, PD-332991 and AZD-5438.

Examples of COX-2 inhibitors include, but are not limited to, celecoxib,parecoxib, deracoxib, ABT-963, etoricoxib, lumiracoxib, BMS-347070, RS57067, NS-398, valdecoxib, rofecoxib, SD-8381,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl-1H-pyrrole, T-614,JTE-522, S-2474, SVT-2016, CT-3 and SC-58125.

Examples of NSAIDs include, but are not limited to, salsalate,diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen,diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac andoxaprozin.

Examples of ErbB2 receptor inhibitors include, but are not limited to,CP-724714, canertinib, trastuzumab, petuzumab, TAK-165, ionafamib,GW-282974, EKB-569, PI-166, dHER2, APC-8024, anti-HER/2neu bispecificantibody B7.her2IgG3 and HER2 trifunctional bispecific antibodies mABAR-209 and mAB 2B-1.

Examples of alkylating agents include, but are not limited to, nitrogenmustard N-oxide, cyclophosphamide, ifosfamide, trofosfamide,chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa,ranimustine, nimustine, Cloretazine™ (laromustine), AMD-473,altretamine, AP-5280, apaziquone, brostallicin, bendamustine,carmustine, estramustine, fotemustine, glufosfamide, KW-2170,mafosfamide, mitolactol, lomustine, treosulfan, dacarbazine andtemozolomide.

Examples of antimetabolites include, but are not limited to,methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil(5-FU) alone or in combination with leucovorin, tegafur, UFT,doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine,S-1, pemetrexed, gemcitabine, fludarabine, 5-azacitidine, capecitabine,cladribine, clofarabine, decitabine, eflornithine, ethenylcytidine,cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine,nolatrexed, disodium pemetrexed, pentostatin, pelitrexol, raltitrexed,triapine, trimetrexate, vidarabine, mycophenolic acid, ocfosfate,pentostatin, tiazofurin, ribavirin, EICAR, hydroxyurea and deferoxamine.

Examples of antibiotics include, but are not limited to, intercalatingantibiotics, aclarubicin, actinomycin D, amrubicin, annamycin,adriamycin, bleomycin, daunorubicin, doxorubicin (including liposomaldoxorubicin), elsamitrucin, epirubicin, glarubicin, idarubicin,mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin,rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin andcombinations thereof.

Examples of topoisomerase inhibiting agents include, but are not limitedto, aclarubicin, amonafide, belotecan, camptothecin,10-hydroxycamptothecin, 9-amino-camptothecin, amsacrine, dexrazoxane,diflomotecan, irinotecan HCl, edotecarin, epirubicin, etoposide,exatecan, becatecarin, gimatecan, lurtotecan, orathecin, BN-80915,mitoxantrone, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,tafluposide and topotecan.

Examples of antibodies include, but are not limited to, rituximab,cetuximab, bevacizumab, trastuzumab, CD40-specific antibodies andIGF1R-specific antibodies, chTNT-1/B, denosumab, edrecolomab, WX G250,zanolimumab, lintuzumab and ticilimumab.

Examples of hormonal therapies include, but are not limited to,sevelamer carbonate, rilostane, luteinizing hormone releasing hormone,modrastane, exemestane, leuprolide acetate, buserelin, cetrorelix,deslorelin, histrelin, anastrozole, fosrelin, goserelin, degarelix,doxercalciferol, fadrozole, formestane, tamoxifen, arzoxifene,bicalutamide, abarelix, triptorelin, finasteride, fulvestrant,toremifene, raloxifene, trilostane, lasofoxifene, letrozole, flutamide,megesterol, mifepristone, nilutamide, dexamethasone, prednisone andother glucocorticoids.

Examples of retinoids or deltoids include, but are not limited to,seocalcitol, lexacalcitol, fenretinide, aliretinoin, tretinoin,bexarotene and LGD-1550.

Examples of plant alkaloids include, but are not limited to,vincristine, vinblastine, vindesine and vinorelbine.

Examples of proteasome inhibitors include, but are not limited to,bortezomib, MG-132, NPI-0052 and PR-171.

Examples of immunologicals include, but are not limited to, interferonsand numerous other immune-enhancing agents. Interferons includeinterferon alpha, interferon alpha-2a, interferon alpha-2b, interferonbeta, interferon gamma-1a, interferon gamma-1b, interferon gamma-n1 andcombinations thereof. Other agents include filgrastim, lentinan,sizofilan, BCG live, ubenimex, WF-10 (tetrachlorodecaoxide or TCDO),aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin,gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, melanomavaccine, molgramostim, sargaramostim, tasonermin, tecleukin, thymalasin,tositumomab, Virulizin™ immunotherapeutic of Lorus Pharmaceuticals,Z-100 (specific substance of Maruyama or SSM), Zevalin™ (90Y-ibritumomabtiuxetan), epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge™(sipuleucel-T), teceleukin, Therocys™ (Bacillus Calmette-Guerin),cytotoxic lymphocyte antigen 4 (CTLA4) antibodies and agents capable ofblocking CTLA4 such as MDX-010.

Examples of biological response modifiers are agents that modify defensemechanisms of living organisms or biological responses, such assurvival, growth, or differentiation of tissue cells to direct them tohave anti-tumor activity. Such agents include, but are not limited to,krestin, lentinan, sizofuran, picibanil, PF-3512676 and ubenimex.

Examples of pyrimidine analogs include, but are not limited to,5-fluorouracil, floxuridine, doxifluridine, raltitrexed, cytarabine,cytosine arabinoside, fludarabine, triacetyluridine, troxacitabine andgemcitabine.

Examples of purine analogs include, but are not limited to,mercaptopurine and thioguanine

Examples of antimitotic agents include, but are not limited to,N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,paclitaxel, docetaxel, larotaxel, epothilone D, PNU-100940, batabulin,ixabepilone, patupilone, XRP-9881, vinflunine and ZK-EPO (syntheticepothilone).

Examples of radiotherapy include, but are not limited to, external beamradiotherapy (XBRT), teletherapy, brachytherapy, sealed-sourceradiotherapy and unsealed-source radiotherapy.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies include, butare not limited to, adecatumumab (Micromet MT201), blinatumomab(Micromet MT103) and the like. Without being limited by theory, one ofthe mechanisms by which T-cells elicit apoptosis of the target cancercell is by exocytosis of cytolytic granule components, which includeperforin and granzyme B. In this regard, Bcl-2 has been shown toattenuate the induction of apoptosis by both perforin and granzyme B.These data suggest that inhibition of Bcl-2 could enhance the cytotoxiceffects elicited by T-cells when targeted to cancer cells (Sutton et al.(1997) J. Immunol. 158:5783-5790).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of the apoptosis-promoting agent ABT-263(Tse et al. (2008) Cancer Res. 68:3421-3428 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising twoheavy-chain DVD polypeptides and two light-chain DVD polypeptides arereferred to as DVD Ig's. Each half of a DVD Ig comprises a heavy-chainDVD polypeptide, a light-chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy-chain variable domain and alight-chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site.

PARP inhibitors include, but are not limited to, ABT-888, olaparib,KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 andthe like.

Additionally or alternatively, a composition of the present inventioncan be administered in combination therapy with one or more antitumoragents selected from ABT-100, N-acetylcolchinol-O-phosphate, acitretin,AE-941, aglycon protopanaxadiol, arglabin, arsenic trioxide, AS04adjuvant-adsorbed HPV vaccine, L-asparaginase, atamestane, atrasentan,AVE-8062, bosentan, canfosfamide, Canvaxin™, catumaxomab, CeaVac™,celmoleukin, combrestatin A4P, contusugene ladenovec, Cotara™,cyproterone, deoxycoformycin, dexrazoxane,N,N-diethyl-2-(4-(phenylmethyl)phenoxy)ethanamine,5,6-dimethylxanthenone-4-acetic acid, docosahexaenoic acid/paclitaxel,discodermolide, efaproxiral, enzastaurin, epothilone B, ethynyluracil,exisulind, falimarev, Gastrimmune™, GMK vaccine, GVAX™, halofuginone,histamine, hydroxycarbamide, ibandronic acid, ibritumomab tiuxetan,IL-13-PE38, inalimarev, interleukin 4, KSB-311, lanreotide,lenalidomide, lonafarnib, lovastatin, 5,10-methylenetetrahydrofolate,mifamurtide, miltefosine, motexafin, oblimersen, OncoVAX™, Osidem™,paclitaxel albumin-stabilized nanoparticle, paclitaxel poliglumex,pamidronate, panitumumab, peginterferon alfa, pegaspargase, phenoxodiol,poly(I)-poly(C12U), procarbazine, ranpirnase, rebimastat, recombinantquadrivalent HPV vaccine, squalamine, staurosporine, STn-KLH vaccine, T4endonuclase V, tazarotene,6,6′,7,12-tetramethoxy-2,2′-dimethyl-1β-berbaman, thalidomide,TNFerade™, ¹³¹I-tositumomab, trabectedin, triazone, tumor necrosisfactor, Ukrain™, vaccinia-MUC-1 vaccine, L-valine-L-boroproline,Vitaxin™, vitespen, zoledronic acid and zorubicin.

In one embodiment, a composition comprising (or prepared using as API)one or more crystalline forms of Compound 1 (including crystallinesalts) is administered in a therapeutically effective amount to asubject in need thereof to treat a disease during which is overexpressedone or more of antiapoptotic Bcl-2 protein, antiapoptotic Bcl-X_(L)protein and antiapoptotic Bcl-w protein.

In another embodiment, a composition comprising (or prepared using asAPI) one or more crystalline forms of Compound 1 (including crystallinesalts) is administered in a therapeutically effective amount to asubject in need thereof to treat a disease of abnormal cell growthand/or dysregulated apoptosis.

Examples of such diseases include, but are not limited to, cancer,mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, ovarian cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, bone cancer, colon cancer, rectalcancer, cancer of the anal region, stomach cancer, gastrointestinal(gastric, colorectal and/or duodenal) cancer, chronic lymphocyticleukemia, esophageal cancer, cancer of the small intestine, cancer ofthe endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, testicular cancer,hepatocellular (hepatic and/or biliary duct) cancer, primary orsecondary central nervous system tumor, primary or secondary braintumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloidleukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,multiple myeloma, oral cancer, non-small-cell lung cancer, prostatecancer, small-cell lung cancer, cancer of the kidney and/or ureter,renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of thecentral nervous system, primary central nervous system lymphoma, nonHodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, adrenocortical cancer, gall bladder cancer, cancer of thespleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastomaor a combination thereof.

In a more particular embodiment, a composition comprising (or preparedusing as API) one or more crystalline forms of Compound 1 (includingcrystalline salts) is administered in a therapeutically effective amountto a subject in need thereof to treat bladder cancer, brain cancer,breast cancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small-cell lung cancer, prostate cancer,small-cell lung cancer or spleen cancer.

According to any of these embodiments, the composition is administeredin combination therapy with one or more additional therapeutic agents.

For example, a method for treating mesothelioma, bladder cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, bone cancer, colon cancer, rectal cancer, cancer of the analregion, stomach cancer, gastrointestinal (gastric, colorectal and/orduodenal) cancer, chronic lymphocytic leukemia, esophageal cancer,cancer of the small intestine, cancer of the endocrine system, cancer ofthe thyroid gland, cancer of the parathyroid gland, cancer of theadrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer ofthe penis, testicular cancer, hepatocellular (hepatic and/or biliaryduct) cancer, primary or secondary central nervous system tumor, primaryor secondary brain tumor, Hodgkin's disease, chronic or acute leukemia,chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia,follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer,prostate cancer, small-cell lung cancer, cancer of the kidney and/orureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasmsof the central nervous system, primary central nervous system lymphoma,non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, adrenocortical cancer, gall bladder cancer, cancer of thespleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastomaor a combination thereof in a subject comprises administering to thesubject therapeutically effective amounts of (a) a compositioncomprising (or prepared using as API) crystalline Compound 1 free baseand (b) one or more of etoposide, vincristine, CHOP, rituximab,rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib.

In particular embodiments, a composition comprising (or prepared usingas API) crystalline Compound 1 free base is administered in atherapeutically effective amount to a subject in need thereof incombination therapy with etoposide, vincristine, CHOP, rituximab,rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in a therapeuticallyeffective amount, for treatment of a lymphoid malignancy such as B-celllymphoma or non-Hodgkin's lymphoma.

In another embodiment, a composition of the invention is administered ina therapeutically effective amount to a subject in need thereof to treatan immune or autoimmune disorder. Such disorders include acquiredimmunodeficiency disease syndrome (AIDS), autoimmune lymphoproliferativesyndrome, hemolytic anemia, inflammatory diseases, thrombocytopenia,acute and chronic immune diseases associated with organ transplantation,Addison's disease, allergic diseases, alopecia, alopecia areata,atheromatous disease/arteriosclerosis, atherosclerosis, arthritis(including osteoarthritis, juvenile chronic arthritis, septic arthritis,Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis-associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycemia, autoimmune neutropenia,autoimmune thrombocytopenia, autoimmune thyroid disease, B-celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy-associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,colorectal common varied immunodeficiency (common variablehypogammaglobulinemia), conjunctivitis, connective tissuedisease-associated interstitial lung disease, contact dermatitis,Coombs-positive hemolytic anemia, cor pulmonale, Creutzfeldt-Jakobdisease, cryptogenic autoimmune hepatitis, cryptogenic fibrosingalveolitis, culture-negative sepsis, cystic fibrosis, cytokinetherapy-associated disorders, Crohn's disease, dementia pugilistica,demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatitisscleroderma, dermatologic conditions,dermatomyositis/polymyositis-associated lung disease, diabetes, diabeticarteriosclerotic disease, diabetes mellitus, diffuse Lewy body disease,dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupuserythematosus, disorders of the basal ganglia, disseminatedintravascular coagulation, Down's Syndrome in middle age, drug-inducedinterstitial lung disease, drug-induced hepatitis, drug-induced movementdisorders induced by drugs which block CNS dopamine receptors, drugsensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy,enteropathic synovitis, epiglottitis, Epstein-Barr virus infection,erythromelalgia, extrapyramidal and cerebellar disorders, familialhematophagocytic lymphohistiocytosis, fetal thymus implant rejection,Friedreich's ataxia, functional peripheral arterial disorders, femaleinfertility, fibrosis, fibrotic lung disease, fungal sepsis, gasgangrene, gastric ulcer, giant cell arteritis, glomerular nephritis,glomerulonephritides, Goodpasture's syndrome, goitrous autoimmunehypothyroidism (Hashimoto's disease), gouty arthritis, graft rejectionof any organ or tissue, graft versus host disease, gram-negative sepsis,gram-positive sepsis, granulomas due to intracellular organisms, group Bstreptococci (GBS) infection, Graves' disease, hemosiderosis-associatedlung disease, hairy cell leukemia, Hallerrorden-Spatz disease,Hashimoto's thyroiditis, hay fever, heart transplant rejection,hemachromatosis, hematopoietic malignancies (leukemia and lymphoma),hemolytic anemia, hemolytic uremic syndrome/thrombolyticthrombocytopenic purpura, hemorrhage, Henoch-Schoenlein purpura,hepatitis A, hepatitis B, hepatitis C, HIV infection/HIV neuropathy,Hodgkin's disease, hypoparathyroidism, Huntington's chorea, hyperkineticmovement disorders, hypersensitivity reactions, hypersensitivitypneumonitis, hyperthyroidism, hypokinetic movement disorders,hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison'sdisease, idiopathic leucopenia, idiopathic pulmonary fibrosis,idiopathic thrombocytopenia, idiosyncratic liver disease, infantilespinal muscular atrophy, infectious diseases, inflammation of the aorta,inflammatory bowel disease, insulin dependent diabetes mellitus,interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis,ischemia-reperfusion injury, ischemic stroke, juvenile perniciousanemia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy,Kaposi's sarcoma, Kawasaki's disease, kidney transplant rejection,legionella, leishmaniasis, leprosy, lesions of the corticospinal system,linear IgA disease, lipidema, liver transplant rejection, Lyme disease,lymphederma, lymphocytic infiltrative lung disease, malaria, maleinfertility idiopathic or NOS, malignant histiocytosis, malignantmelanoma, meningitis, meningococcemia, microscopic vasculitis of thekidneys, migraine headache, mitochondrial multisystem disorder, mixedconnective tissue disease, mixed connective tissue disease-associatedlung disease, monoclonal gammopathy, multiple myeloma, multiple systemsdegenerations (Mencel, Dejerine-Thomas, Shy-Drager and Machado-Joseph),myalgic encephalitis/Royal Free Disease, myasthenia gravis, microscopicvasculitis of the kidneys, mycobacterium avium intracellulare,mycobacterium tuberculosis, myelodyplastic syndrome, myocardialinfarction, myocardial ischemic disorders, nasopharyngeal carcinoma,neonatal chronic lung disease, nephritis, nephrosis, nephrotic syndrome,neurodegenerative diseases, neurogenic I muscular atrophies, neutropenicfever, non-alcoholic steatohepatitis, occlusion of the abdominal aortaand its branches, occlusive arterial disorders, organ transplantrejection, orchitis/epidydimitis, orchitis/vasectomy reversalprocedures, organomegaly, osteoarthrosis, osteoporosis, ovarian failure,pancreas transplant rejection, parasitic diseases, parathyroidtransplant rejection, Parkinson's disease, pelvic inflammatory disease,pemphigus vulgaris, pemphigus foliaceus, pemphigoid, perennial rhinitis,pericardial disease, peripheral atherlosclerotic disease, peripheralvascular disorders, peritonitis, pernicious anemia, phacogenic uveitis,pneumocystis carinii pneumonia, pneumonia, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), post-perfusion syndrome, post-pump syndrome,post-MI cardiotomy syndrome, postinfectious interstitial lung disease,premature ovarian failure, primary biliary cirrhosis, primary sclerosinghepatitis, primary myxoedema, primary pulmonary hypertension, primarysclerosing cholangitis, primary vasculitis, progressive supranuclearpalsy, psoriasis, psoriasis type 1, psoriasis type 2, psoriaticarthropathy, pulmonary hypertension secondary to connective tissuedisease, pulmonary manifestation of polyarteritis nodosa,post-inflammatory interstitial lung disease, radiation fibrosis,radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease,Refsum's disease, regular narrow QRS tachycardia, Reiter's disease,renal disease NOS, renovascular hypertension, reperfusion injury,restrictive cardiomyopathy, rheumatoid arthritis-associated interstitiallung disease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,scleroderma, senile chorea, senile dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease-associated lung disease, Sjögren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthropathy, sporadicpolyglandular deficiency type I, sporadic polyglandular deficiency typeII, Still's disease, streptococcal myositis, stroke, structural lesionsof the cerebellum, subacute sclerosing panencephalitis, sympatheticophthalmia, syncope, syphilis of the cardiovascular system, systemicanaphylaxis, systemic inflammatory response syndrome, systemic onsetjuvenile rheumatoid arthritis, systemic lupus erythematosus, systemiclupus erythematosus-associated lung disease, systemic sclerosis,systemic sclerosis-associated interstitial lung disease, T-cell or FABALL, Takayasu's disease/arteritis, telangiectasia, Th2-type and Th1-typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and fungal infections, vital encephalitis/aseptic meningitis,vital-associated hemaphagocytic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

The present invention also provides a method for maintaining inbloodstream of a human cancer patient a therapeutically effective plasmaconcentration of Compound 1 and/or one or more metabolites thereof,comprising administering to the subject a pharmaceutical composition asdescribed herein, in a dosage amount equivalent to about 50 to about 500mg Compound 1 per day, at an average dosage interval of about 3 hours toabout 7 days.

What constitutes a therapeutically effective plasma concentrationdepends inter alia on the particular cancer present in the patient, thestage, severity and aggressiveness of the cancer, and the outcome sought(e.g., stabilization, reduction in tumor growth, tumor shrinkage,reduced risk of metastasis, etc.). It is strongly preferred that, whilethe plasma concentration is sufficient to provide benefit in terms oftreating the cancer, it should not be sufficient to provoke an adverseside-effect to an unacceptable or intolerable degree.

For treatment of cancer in general and of a lymphoid malignancy such asnon-Hodgkin's lymphoma in particular, the plasma concentration ofCompound 1 should in most cases be maintained in a range of about 0.5 toabout 10 μg/ml. Thus, during a course of Compound 1 therapy, thesteady-state C_(max) should in general not exceed about 10 μg/ml, andthe steady-state C_(min) should in general not fall below about 0.5μg/ml. It will further be found desirable to select, within the rangesprovided above, a daily dosage amount and average dosage intervaleffective to provide a C_(max)/C_(min) ratio not greater than about 5,for example not greater than about 3, at steady-state. It will beunderstood that longer dosage intervals will tend to result in greaterC_(max)/C_(min) ratios. Illustratively, at steady-state, an Compound 1C_(max) of about 3 to about 8 μg/ml and C_(min) of about 1 to about 5μg/ml can be targeted by the present method.

A daily dosage amount effective to maintain a therapeutically effectiveCompound 1 plasma level is, according to the present embodiment, about50 to about 1000 mg. In most cases a suitable daily dosage amount isabout 200 to about 400 mg. Illustratively, the daily dosage amount canbe for example about 50, about 100, about 150, about 200, about 250,about 300, about 350, about 400, about 450, about 500, about 750 orabout 1000 mg.

An average dosage interval effective to maintain a therapeuticallyeffective Compound 1 plasma level is, according to the presentembodiment, about 3 hours to about 7 days. In most cases, a suitableaverage dosage interval is about 8 hours to about 3 days, or about 12hours to about 2 days. A once-daily (q.d.) administration regimen isoften suitable.

As in other embodiments, administration according to the presentembodiment can be with or without food, i.e., in a non-fasting orfasting condition. It is generally preferred to administer the presentcompositions to a non-fasting patient.

When introducing elements of the present disclosure or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

As various changes could be made in the above described methods and/orcompositions without departing from the scope of the disclosure, it isintended that all matter contained in the above description and shown inthe accompanying figures shall be interpreted as illustrative and not beviewed in a limiting sense.

What is claimed is:
 1. A compound having the systematic name4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide(Compound 1) in a salt or crystalline form.
 2. The compound of claim 1,wherein the crystalline form is Compound 1 free base anhydrate,characterized by a powder X-ray diffraction pattern having at least onepeak selected from those at 6.3, 7.1, 9.0, 9.5, 12.5, 14.5, 14.7, 15.9,16.9, and 18.9 degrees 2θ (pattern A), each peak being ±0.2 degrees 2θ,when measured at about 25° C. with Cu K_(α) radiation at 1.54178 Å. 3.The compound of claim 1, wherein the crystalline form is Compound 1 freebase anhydrate, characterized by a powder X-ray diffraction patternhaving at least one peak selected from those at 5.8, 7.7, 8.3, 9.9,13.0, 13.3, 14.2, 15.3, 16.6, 17.9, 18.3, 19.8, 20.7, 21.2, 21.9, 22.5,23.6, and 24.1 degrees 2θ (pattern B), each peak being ±0.2 degrees 2θ,when measured at about 25° C. with Cu K_(α) radiation at 1.54178 Å. 4.The compound of claim 1, wherein the crystalline form is Compound 1 freebase hydrate, characterized by a powder X-ray diffraction pattern havingat least one peak selected from those at 5.8, 7.6, 7.9, 10.7, 11.7,14.0, 15.3, 15.8, 17.4, 18.3, 19.9, 20.4, 20.7, 22.5, 24.9, 25.8, and26.7 degrees 2θ (pattern C), each peak being ±0.2 degrees 2θ, whenmeasured at about 25° C. with radiation at 1.54178 Å. Cu K_(α) radiationat 1.54178 Å.
 5. The compound of claim 1, wherein the crystalline formis Compound 1 free base hydrate, characterized by a powder X-raydiffraction pattern having at least one peak selected from those at 3.3,6.4, 7.1, 7.3, 10.1, 11.4, 13.2, 14.4, 14.6, 15.1, 15.8, 16.2, 17.2,17.6, 18.0, 18.6, 19.0, 19.5, 19.8, 20.2, 20.7, 21.0, 22.5, 23.0, 26.0,28.9, and 29.2 degrees 2θ (pattern D), each peak being ±0.2 degrees 2θ,when measured at about 25° C. with Cu K_(α) radiation at 1.54178 Å. 6.The compound of claim 1, wherein the crystalline form is Compound 1 freebase dichloromethane solvate, characterized by a powder X-raydiffraction pattern having at least one peak selected from those at 5.9,7.1, 9.6, 10.0, 10.7, 11.1, 13.2, 14.8, and 18.2 degrees 2θ, each peakbeing ±0.2 degrees 2θ (pattern E), when measured at about 25° C. with CuK_(α) radiation at 1.54178 Å.
 7. The compound of claim 1, wherein thecrystalline form is Compound 1 free base dichloromethane solvate,characterized by a monoclinic lattice type and P21/n space group havingunit cell lengths for the three axes of about (a) 13.873 Å, (b) 12.349Å, (c) 29.996 Å and the three unit cell angles of about (α) 90.00°, (β)92.259°, and (γ) 90.00°.
 8. The compound of claim 1, wherein thecrystalline form is Compound 1 free base ethyl acetate solvate,characterized by a powder X-ray diffraction pattern having at least onepeak selected from those at 5.8, 7.1, 9.5, 9.9, 10.6, 11.6, 13.1, 13.8,14.8, 16.0, 17.9, 20.2, 21.2, 23.2, 24.4, and 26.4 degrees 2θ (patternF), each peak being ±0.2 degrees 2θ, when measured at about 25° C. withCu K_(α) radiation at 1.54178 Å.
 9. The compound of claim 1, wherein thecrystalline form is Compound 1 free base ethyl acetate solvate,characterized by a powder X-ray diffraction pattern having at least onepeak selected from those at 3.3, 6.5, 7.0, 7.3, 9.2, 9.7, 11.2, 11.4,11.9, 12.9, 14.4, 14.9, 15.8, 16.2, 17.2, 17.4, 17.8, 18.5, 18.9, 19.4,20.1, 20.7, 20.9, 22.0, 22.7, 23.4, 23.8, 24.7, 25.9, 27.0, and 28.9degrees 2θ (pattern G), each peak being ±0.2 degrees 2θ, when measuredat about 25° C. with radiation at 1.54178 Å.
 10. The compound of claim1, wherein the crystalline form is Compound 1 free base acetonitrilesolvate, characterized by a powder X-ray diffraction pattern having atleast one peak selected from those at 5.8, 7.4, 7.6, 10.2, 13.0, 13.6,14.9, 16.4, 17.0, 17.5, 18.2, 19.4, 19.7, 20.4, 21.0, 21.2, 21.8, 22.4,22.9, 24.2, 24.3, 26.1, and 29.2 degrees 2θ (pattern H), each peak being±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178Å.
 11. The compound of claim 1, wherein the crystalline form is Compound1 free base acetonitrile solvate, characterized by a triclinic latticetype and P1 space group having unit cell lengths for the three axes ofabout (a) 12.836 Å, (b) 13.144 Å, (c) 15.411 Å and the three unit cellangles of about (α) 92.746°, (β) 95.941°, and (γ) 113.833°.
 12. Thecompound of claim 1, wherein the crystalline form is Compound 1 freebase acetonitrile solvate, characterized by a powder X-ray diffractionpattern having at least one peak selected from those at 6.4, 6.9, 7.7,8.8, 9.4, 11.1, 12.3, 12.8, 16.5, 17.0, 17.4, 18.3, 18.6, 19.0, 19.2,20.3, 21.6, 22.3, 22.9, and 23.7 degrees 2θ (pattern I), each peak being±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178Å.
 13. The compound of claim 1, wherein the crystalline form is Compound1 free base acetone solvate, characterized by a powder X-ray diffractionpattern having at least one peak selected from those at 6.0, 6.8, 8.0,9.0, 9.7, 11.2, 11.9, 12.6, 14.7, 15.0, 15.2, 15.8, 16.4, 16.6, 17.6,17.8, 17.9, 18.7, 20.2, 20.8, 21.6, 22.2, 22.6, 23.3, 23.8, 24.0, 24.4,26.8, 27.1, 28.0, and 28.2 degrees 2θ (pattern J), each peak being ±0.2degrees 2θ, when measured at about 25° C. with radiation at 1.54178 Å.14. The compound of claim 1, wherein the crystalline form is Compound 1hydrochloride, characterized by a powder X-ray diffraction patternhaving at least one peak selected from those at 5.1, 5.9, 7.7, 9.9,10.2, 10.8, 13.6, 14.0, 15.4, 15.9, 16.2, 17.6, 18.3, 18.7, 19.7, 19.9,20.1, 20.4, 20.7, 20.9, 22.9, and 26.2 degrees 2θ (Pattern K), each peakbeing ±0.2 degrees 2θ, when measured at about 25° C. with Cu K_(α)radiation at 1.54178 Å.
 15. The compound of claim 1, wherein thecrystalline form is Compound 1 free base hydrochloride, characterized bya triclinic lattice type and P1 space group having unit cell lengths forthe three axes of about (a) 10.804 Å, (b) 12.372 Å, (c) 19.333 Å and thethree unit cell angles of about (α) 76.540°, (β) 87.159°, and (γ)70.074°.
 16. The compound of claim 1, wherein the crystalline form isCompound 1 free base hydrochloride hydrate, characterized by a powderX-ray diffraction pattern having at least one peak selected from thoseat 4.6, 8.7, 9.6, 9.9, 12.3, 14.9, 15.7, 17.6, 18.1, 18.4, 19.3, 19.6,21.0, 23.3, 23.9, 24.8, 26.5, 27.2, 27.4, 29.0, and 30.1 degrees 2θ(pattern L), each peak being ±0.2 degrees 2θ, when measured at about 25°C. with Cu K_(α) radiation at 1.54178 Å.
 17. The compound of claim 1,wherein the crystalline form is Compound 1 free base sulfate,characterized by a powder X-ray diffraction pattern having at least onepeak selected from those at 4.8, 7.7, 8.3, 9.7, 10.2, 12.0, 12.6, 14.5,15.4, 17.4, 17.9, 18.4, 19.1, 19.5, 21.0, 22.4, 23.3, 23.9, 25.1, and26.8 degrees 2θ (pattern M), each peak being ±0.2 degrees 2θ, whenmeasured at about 25° C. with Cu K_(α) radiation at 1.54178 Å.
 18. Thecompound of claim 1, wherein the crystalline form is Compound 1 freebase tetrahydrofuran, characterized by a powder X-ray diffractionpattern having a least one peak selected from those at 4.0, 4.6, 8.0,8.5, 9.4, 14.6, 17.1, 17.4, 17.8, 18.1, 19.2, 19.5, 20.1, 20.4, 20.5,and 21.7 degrees 2θ (pattern N), each peak being ±0.2 degrees 2θ, whenmeasured at about 25° C. with Cu K_(α) radiation at 1.54178 Å.
 19. Apharmaceutical composition comprising a compound of claim 1 and one ormore pharmaceutically acceptable excipients.
 20. A pharmaceuticalcomposition comprising a compound of claim 2 and one or morepharmaceutically acceptable excipients.
 21. A pharmaceutical compositioncomprising a compound of claim 3 and one or more pharmaceuticallyacceptable excipients.
 22. A pharmaceutical composition comprising acompound of claim 4 and one or more pharmaceutically acceptableexcipients.
 23. A pharmaceutical composition comprising a compound ofclaim 5 and one or more pharmaceutically acceptable excipients.
 24. Apharmaceutical composition comprising a compound of claim 6 and one ormore pharmaceutically acceptable excipients.
 25. A pharmaceuticalcomposition comprising a compound of claim 7 and one or morepharmaceutically acceptable excipients.
 26. A pharmaceutical compositioncomprising a compound of claim 8 and one or more pharmaceuticallyacceptable excipients.
 27. A pharmaceutical composition comprising acompound of claim 9 and one or more pharmaceutically acceptableexcipients.
 28. A pharmaceutical composition comprising a compound ofclaim 10 and one or more pharmaceutically acceptable excipients.
 29. Apharmaceutical composition comprising a compound of claim 11 and one ormore pharmaceutically acceptable excipients.
 30. A pharmaceuticalcomposition comprising a compound of claim 12 and one or morepharmaceutically acceptable excipients.
 31. A pharmaceutical compositioncomprising a compound of claim 13 and one or more pharmaceuticallyacceptable excipients.
 32. A pharmaceutical composition comprising acompound of claim 14 and one or more pharmaceutically acceptableexcipients.
 33. A pharmaceutical composition comprising a compound ofclaim 15 and one or more pharmaceutically acceptable excipients.
 34. Apharmaceutical composition comprising a compound of claim 16 and one ormore pharmaceutically acceptable excipients.
 35. A pharmaceuticalcomposition comprising a compound of claim 17 and one or morepharmaceutically acceptable excipients.
 36. A pharmaceutical compositioncomprising a compound of claim 18 and one or more pharmaceuticallyacceptable excipients.
 37. A process for preparing a pharmaceuticalsolution of Compound 1 comprising dissolving a compound of claim 1 in apharmaceutically acceptable solvent or mixture of solvents.
 38. Aprocess for preparing a pharmaceutical solution of Compound 1 comprisingdissolving a compound of claim 2 in a pharmaceutically acceptablesolvent or mixture of solvents.
 39. A process for preparing apharmaceutical solution of Compound 1 comprising dissolving a compoundof claim 3 in a pharmaceutically acceptable solvent or mixture ofsolvents.
 40. A process for preparing a pharmaceutical solution ofCompound 1 comprising dissolving a compound of claim 4 in apharmaceutically acceptable solvent or mixture of solvents.
 41. Aprocess for preparing a pharmaceutical solution of Compound 1 comprisingdissolving a compound of claim 5 in a pharmaceutically acceptablesolvent or mixture of solvents.
 42. A process for preparing apharmaceutical solution of Compound 1 comprising dissolving a compoundof claim 6 in a pharmaceutically acceptable solvent or mixture ofsolvents.
 43. A process for preparing a pharmaceutical solution ofCompound 1 comprising dissolving a compound of claim 7 in apharmaceutically acceptable solvent or mixture of solvents.
 44. Aprocess for preparing a pharmaceutical solution of Compound 1 comprisingdissolving a compound of claim 8 in a pharmaceutically acceptablesolvent or mixture of solvents.
 45. A process for preparing apharmaceutical solution of Compound 1 comprising dissolving a compoundof claim 9 in a pharmaceutically acceptable solvent or mixture ofsolvents.
 46. A process for preparing a pharmaceutical solution ofCompound 1 comprising dissolving a compound of claim 10 in apharmaceutically acceptable solvent or mixture of solvents.
 47. Aprocess for preparing a pharmaceutical solution of Compound 1 comprisingdissolving a compound of claim 11 in a pharmaceutically acceptablesolvent or mixture of solvents.
 48. A process for preparing apharmaceutical solution of Compound 1 comprising dissolving a compoundof claim 12 in a pharmaceutically acceptable solvent or mixture ofsolvents.
 49. A process for preparing a pharmaceutical solution ofCompound 1 comprising dissolving a compound of claim 13 in apharmaceutically acceptable solvent or mixture of solvents.
 50. Aprocess for preparing a pharmaceutical solution of Compound 1 comprisingdissolving a compound of claim 14 in a pharmaceutically acceptablesolvent or mixture of solvents.
 51. A process for preparing apharmaceutical solution of Compound 1 comprising dissolving a compoundof claim 15 in a pharmaceutically acceptable solvent or mixture ofsolvents.
 52. A process for preparing a pharmaceutical solution ofCompound 1 comprising dissolving a compound of claim 16 in apharmaceutically acceptable solvent or mixture of solvents.
 53. Aprocess for preparing a pharmaceutical solution of Compound 1 comprisingdissolving a compound of claim 17 in a pharmaceutically acceptablesolvent or mixture of solvents.
 54. A process for preparing apharmaceutical solution of Compound 1 comprising dissolving a compoundof claim 18 in a pharmaceutically acceptable solvent or mixture ofsolvents.
 55. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering to a subject having the disease atherapeutically effective amount of (a) a compound of claim 1 or (b) apharmaceutical composition comprising a compound of claim 1 and one ormore pharmaceutically acceptable excipients.
 56. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 2 or (b) a pharmaceutical composition comprising acompound of claim 2 and one or more pharmaceutically acceptableexcipients.
 57. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 3 or (b) apharmaceutical composition comprising a compound of claim 3 and one ormore pharmaceutically acceptable excipients.
 58. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 4 or (b) a pharmaceutical composition comprising acompound of claim 4 and one or more pharmaceutically acceptableexcipients.
 59. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 5 or (b) apharmaceutical composition comprising a compound of claim 5 and one ormore pharmaceutically acceptable excipients.
 60. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 6 or (b) a pharmaceutical composition comprising acompound of claim 6 and one or more pharmaceutically acceptableexcipients.
 61. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 7 or (b) apharmaceutical composition comprising a compound of claim 7 and one ormore pharmaceutically acceptable excipients.
 62. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 8 or (b) a pharmaceutical composition comprising acompound of claim 8 and one or more pharmaceutically acceptableexcipients.
 63. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 9 or (b) apharmaceutical composition comprising a compound of claim 9 and one ormore pharmaceutically acceptable excipients.
 64. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 10 or (b) a pharmaceutical composition comprising acompound of claim 10 and one or more pharmaceutically acceptableexcipients.
 65. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 11 or (b)a pharmaceutical composition comprising a compound of claim 11 and oneor more pharmaceutically acceptable excipients.
 66. A method fortreating a disease characterized by apoptotic dysfunction and/oroverexpression of an anti-apoptotic Bcl-2 family protein, comprisingadministering to a subject having the disease a therapeuticallyeffective amount of (a) a compound of claim 12 or (b) a pharmaceuticalcomposition comprising a compound of claim 12 and one or morepharmaceutically acceptable excipients.
 67. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 13 or (b) a pharmaceutical composition comprising acompound of claim 13 and one or more pharmaceutically acceptableexcipients.
 68. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 14 or (b)a pharmaceutical composition comprising a compound of claim 14 and oneor more pharmaceutically acceptable excipients.
 69. A method fortreating a disease characterized by apoptotic dysfunction and/oroverexpression of an anti-apoptotic Bcl-2 family protein, comprisingadministering to a subject having the disease a therapeuticallyeffective amount of (a) a compound of claim 15 or (b) a pharmaceuticalcomposition comprising a compound of claim 15 and one or morepharmaceutically acceptable excipients.
 70. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering to asubject having the disease a therapeutically effective amount of (a) acompound of claim 16 or (b) a pharmaceutical composition comprising acompound of claim 16 and one or more pharmaceutically acceptableexcipients.
 71. A method for treating a disease characterized byapoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2family protein, comprising administering to a subject having the diseasea therapeutically effective amount of (a) a compound of claim 17 or (b)a pharmaceutical composition comprising a compound of claim 17 and oneor more pharmaceutically acceptable excipients.
 72. A method fortreating a disease characterized by apoptotic dysfunction and/oroverexpression of an anti-apoptotic Bcl-2 family protein, comprisingadministering to a subject having the disease a therapeuticallyeffective amount of (a) a compound of claim 18 or (b) a pharmaceuticalcomposition comprising a compound of claim 18 and one or morepharmaceutically acceptable excipients.
 73. The method of claim 55,wherein the compound or pharmaceutical composition is administered by anoral, parenteral, sublingual, buccal, intranasal, pulmonary, topical,transdermal, intradermal, ocular, otic, rectal, vaginal, intragastric,intracranial, intrasynovial or intra-articular route.
 74. The method ofclaim 55, wherein the disease is a neoplastic, immune, or autoimmunedisease.
 75. The method of claim 74, wherein the neoplastic disease isselected from the group consisting of cancer, mesothelioma, bladdercancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, ovarian cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, bone cancer, colon cancer, rectal cancer, cancer of theanal region, stomach cancer, gastrointestinal (gastric, colorectaland/or duodenal) cancer, chronic lymphocytic leukemia, esophagealcancer, cancer of the small intestine, cancer of the endocrine system,cancer of the thyroid gland, cancer of the parathyroid gland, cancer ofthe adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancerof the penis, testicular cancer, hepatocellular (hepatic and/or biliaryduct) cancer, primary or secondary central nervous system tumor, primaryor secondary brain tumor, Hodgkin's disease, chronic or acute leukemia,chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia,follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer,prostate cancer, small-cell lung cancer, cancer of the kidney and/orureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasmsof the central nervous system, primary central nervous system lymphoma,non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, adrenocortical cancer, gall bladder cancer, cancer of thespleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastomaand combinations thereof.
 76. The method of claim 74, wherein theneoplastic disease is a lymphoid malignancy.
 77. The method of claim 76,wherein the lymphoid malignancy is non-Hodgkin's lymphoma, chroniclymphoid leukemia, or acute lymphocytic leukemia.
 78. The method ofclaim 55, wherein the therapeutically effective amount is administeredorally in a dose of about 50 to about 1000 mg Compound 1 per day at anaverage treatment interval of about 3 hours to about 7 days.
 79. Themethod of claim 55, wherein the therapeutically effective amount isadministered orally once daily in a dose of about 200 to about 400 mgCompound 1 free base equivalent per day.
 80. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 1 to a subject having thedisease.
 81. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 2 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 82. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 3 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 83. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 4 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 84. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 5 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 85. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 6 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 86. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 7 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 87. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 8 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 88. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 9 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 89. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 10 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 90. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 11 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 91. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 12 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 92. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 13 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 93. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 14 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 94. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 15 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 95. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 16 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 96. A method for treating adisease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, comprising administering asolution or dispersion of a compound of claim 17 in a pharmaceuticallyacceptable solvent or mixture of solvents to a subject having thedisease.
 97. A method for treating a disease characterized by apoptoticdysfunction and/or overexpression of an anti-apoptotic Bcl-2 familyprotein, comprising administering a solution or dispersion of a compoundof claim 18 in a pharmaceutically acceptable solvent or mixture ofsolvents to a subject having the disease.
 98. The method of claim 80,wherein the solution is administered by an oral, parenteral, sublingual,buccal, intranasal, pulmonary, topical, transdermal, intradermal,ocular, otic, rectal, vaginal, intragastric, intracranial, intrasynovialor intra-articular route.
 99. The method of claim 80, wherein thedisease is a neoplastic, immune, or autoimmune disease.
 100. The methodof claim 99, wherein the neoplastic disease is selected from the groupconsisting of cancer, mesothelioma, bladder cancer, pancreatic cancer,skin cancer, cancer of the head or neck, cutaneous or intraocularmelanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma ofthe fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer,colon cancer, rectal cancer, cancer of the anal region, stomach cancer,gastrointestinal (gastric, colorectal and/or duodenal) cancer, chroniclymphocytic leukemia, esophageal cancer, cancer of the small intestine,cancer of the endocrine system, cancer of the thyroid gland, cancer ofthe parathyroid gland, cancer of the adrenal gland, sarcoma of softtissue, cancer of the urethra, cancer of the penis, testicular cancer,hepatocellular (hepatic and/or biliary duct) cancer, primary orsecondary central nervous system tumor, primary or secondary braintumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloidleukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,multiple myeloma, oral cancer, non-small-cell lung cancer, prostatecancer, small-cell lung cancer, cancer of the kidney and/or ureter,renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of thecentral nervous system, primary central nervous system lymphoma, nonHodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, adrenocortical cancer, gall bladder cancer, cancer of thespleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastomaand combinations thereof.
 101. The method of claim 99, wherein theneoplastic disease is a lymphoid malignancy.
 102. The method of claim101, wherein the lymphoid malignancy is non-Hodgkin's lymphoma, chroniclymphoid leukemia, or acute lymphocytic leukemia.
 103. The method ofclaim 80, wherein the solution is administered orally in a dose of about50 to about 1000 mg Compound 1 per day at an average treatment intervalof about 3 hours to about 7 days.
 104. The method of claim 80, whereinthe solution is administered orally once daily in a dose of about 200 toabout 400 mg Compound 1 free base equivalent per day.
 105. Compound 1hydrochloride.
 106. Compound 1 sulfate.